JP2010517980A - Use of 7-azaindole in the inhibition of c-Jun N-terminal kinase - Google Patents

Abstract

  The present invention relates to compounds of formula (I) in inhibiting c-Jun N-terminal kinase (JNK) activity and in particular in the treatment of neurodegenerative disorders, inflammatory diseases and / or autoimmune diseases, or pharmaceutically acceptable Its salt provided. The present invention also provides a process for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof and a composition containing them.

Description

  The present invention relates to 7-azaindole derivatives or pharmaceutically acceptable salts thereof, their use in inhibiting c-Jun N-terminal kinase (JNK) activity, pharmaceuticals and in particular neurodegenerative disorders, inflammatory diseases, autoimmunity It relates to their use in the treatment of diseases and / or organ failure. The present invention also provides a process for producing the 7-azaindole derivatives and compositions containing them.

  c-Jun N-terminal kinase (hereinafter referred to as “JNK”) is a member of the serine / threonine protein kinase family and the mitogen-activated protein kinase (MAPK) family. Three different genes (JNK1, JNK2 and JNK3) have been identified.

  JNK is known to be associated with neurodegenerative disorders such as multiple sclerosis and autoimmune diseases such as rheumatoid arthritis (WO 2004/078756).

  Furthermore, the above patent document also discloses that 7-azaindole derivatives having a ring at the C3 position and an aromatic group such as a phenyl group at the C5 position, or a heterocyclic group such as a morpholino group have JNK inhibitory activity. ing.

  In addition, certain 7-azaindole derivatives having a substitution at the C3 position (eg, thiazolyl group) and a substitution at the C5 position (eg, a heterocyclic group) have in vitro inhibitory activity against other kinases, ie, TEC and JAK kinases. (WO 2006/004984).

  However, there is no disclosure of 7-azaindole derivatives having a thiazolyl group at the C3 position and a non-aromatic carbocyclic group at the C5 position.

  There is a need for JNK inhibitors that have superior selectivity for JNK over other kinases. This is to reduce the risk of unexpected side effects.

  Under these circumstances, the inventors have conducted thorough research. As a result, the present inventors have shown that 7-azaindole derivatives having a thiazolyl group at the C3 position and a non-aromatic hydrocarbon ring group at the C5 position (I) have superior selectivity for JNK kinases over other kinases. And found to have significant in vivo activity, thereby completing the present invention.

FIG. 1 shows the effect of (I-60) (40 mg / kg po once / day) on peak disease scores in mouse EAE experiments. FIG. 2 shows the effect of (I-60) (40 mg / kg po once / day) on animal body weight in mouse EAE experiments. FIG. 3 shows the effect of reference compound A (20 mg / kg po once / day) on peak disease scores in mouse EAE experiments. FIG. 4 shows the effect of Reference Compound A (20 mg / kg po once / day) on animal body weight in mouse EAE experiments.

Accordingly, a first aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

Where
Ring X represents a thiazole ring,
R ¹ is a halogen atom, an oxo group, an ethylenedioxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 hydroxyalkyl group, —C (O) OH, (C _1-6 alkyl) 5-7 membered non-aromatic optionally substituted independently with 1 to 4 substituents selected from the group consisting of amino groups, di (C _1-6 alkyl) amino groups and -Ra-Rb Represents a hydrocarbon ring group,
R ^a represents a single bond or —CH ₂ —;
R ^b is a 4- to 7-membered non-aromatic heterocyclic group optionally and independently substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C _1-6 alkyl group; Represents a C _6-10 aryl group or a 5-6 membered heteroaryl group,
R ² represents a single bond or a carbonyl group,
R ³ represents hydrogen, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 haloalkyl group, a di (C _1-6 alkyl) amino group, or a 4-7 membered non-aromatic heterocycle. Represents a cyclic group, wherein at least one ring heteroatom is a nitrogen atom optionally and independently substituted with 1 to 4 C _1-6 alkyl groups;
R ⁴ represents hydrogen or a C _1-6 alkyl group.

In a preferred feature of the first aspect of the invention, the compound of formula (I) is a compound of formula (Ia):

Where
Ring X represents a thiazole ring,
R ¹ is a halogen atom, an oxo group, an ethylenedioxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 hydroxyalkyl group, —C (O) OH, (C _1-6 alkyl) 5-7 membered non-aromatic optionally substituted independently with 1 to 4 substituents selected from the group consisting of amino groups, di (C _1-6 alkyl) amino groups and -Ra-Rb Represents a hydrocarbon ring group,
R ^a represents a single bond or —CH ₂ —;
R ^b is a 4- to 7-membered non-aromatic heterocyclic group optionally and independently substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C _1-6 alkyl group; Represents a C _6-10 aryl group or a 5-6 membered heteroaryl group,
R ² represents a single bond or a carbonyl group,
R ³ represents a hydroxyl group, a di (C _1-6 alkyl) amino group or a 4-7 membered non-aromatic heterocyclic group, wherein at least one ring heteroatom is 1 to 4 C A nitrogen atom optionally and independently substituted with _{1 to 6} alkyl groups.

Preferably, R ¹ is a halogen atom, an oxo group, an ethylenedioxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 hydroxyalkyl group, —C (O) OH and —R ^a. -Represents a 5- to 7-membered non-aromatic hydrocarbon ring group optionally and independently substituted with 1 to 4 substituents selected from the group consisting of R ^b , wherein R ^a and R ^b are the above As defined in.

In a preferred embodiment, R ¹ is a halogen atom, an oxo group, an ethylenedioxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 hydroxyalkyl group, —C (O) OH, ( Optionally substituted independently with 1 to 4 substituents selected from the group consisting of C _1-6 alkyl) amino group, di (C _1-6 alkyl) amino group and —R ^a —R ^b Represents a cyclopentyl group, a cyclohexyl group, a cyclopentenyl group, a cyclohexenyl group or a cyclohexadienyl group;
R ^a represents a single bond or —CH ₂ —;
R ^b is a 4- to 7-membered non-aromatic heterocyclic group optionally and independently substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C _1-6 alkyl group; C represents a _6-10 aryl group or a 5-6 membered heteroaryl group.

Preferably, R ¹ is a cyclopentyl group, cyclohexyl, optionally and independently substituted with 1 to 4 substituents selected from the group consisting of an ethylenedioxy group, a C _1-6 alkyl group and a morpholino group Represents a group, a cyclopentenyl group, a cyclohexenyl group or a cyclohexadienyl group.

In a preferred embodiment, R ² represents a single bond.

In an alternative preferred embodiment, R ² represents a carbonyl group.

In preferred embodiments, R ³ is hydrogen, optionally and independently substituted with a C _1-6 alkyl group, methyl group, methoxy group, ethoxy group, trifluoromethyl group, dimethylamino group, piperidyl group, piperazinyl Represents a group or a morpholino group.

R ⁴ preferably represents hydrogen or methyl.

In a second aspect, the present invention relates to a compound selected from the following group or a pharmaceutically acceptable salt thereof.

In a third aspect, the present invention provides a pharmaceutical composition comprising a compound as defined herein.

  In a fourth aspect, the present invention provides a compound or pharmaceutical composition as defined herein for use in medicine.

  In a fifth aspect, the invention provides a compound or pharmaceutical composition as defined herein for use in preventing and / or treating neurodegenerative disorders, inflammatory diseases, autoimmune diseases and / or organ failure. Offer things. Preferably, the neurodegenerative disorder is multiple sclerosis. Preferably, the inflammatory disease is multiple sclerosis. Preferably, the autoimmune disease is rheumatoid arthritis. Preferably, the organ failure is heart failure, liver failure or diabetic nephropathy.

  In a sixth aspect, the invention provides a neurodegenerative disorder (eg, multiple sclerosis), an inflammatory disease (eg, multiple sclerosis), an autoimmune disease (eg, rheumatoid arthritis) and / or organ failure ( For example, a method for preventing and / or treating heart failure, liver failure or diabetic nephropathy) wherein a therapeutically effective amount of a compound as defined herein or a pharmaceutical salt or composition thereof is administered to a mammal A method comprising administering to

  In a seventh aspect, the invention provides a neurodegenerative disorder (eg, multiple sclerosis), an inflammatory disease (eg, multiple sclerosis), an autoimmune disease (eg, rheumatoid arthritis) and / or organ failure ( For example, provided is the use of a compound as defined herein or a pharmaceutical salt thereof for the manufacture of a medicament for preventing and / or treating heart failure, liver failure or diabetic nephropathy).

  The present invention further provides a process for preparing compounds of formula (I) and intermediates involved in the preparation of compounds of formula (I). The methods for preparing the compounds and intermediates are described below in Reaction Schemes 1 to 8 and illustrated in the accompanying examples.

  The meanings of symbols and terms used in the specification of the present application are explained below, and the present invention is described in detail.

  The compounds of the invention are provided for the prevention and / or treatment of neurodegenerative disorders, inflammatory diseases and / or autoimmune diseases and / or organ failure.

  Examples of “neurodegenerative disorders” as used herein include multiple sclerosis, dementia; Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; Huntington's disease; senile chorea; Head and spinal cord trauma including head trauma; acute and chronic pain; epilepsy and seizures; olive bridge cerebellar dementia; neuronal cell death; hypoxia-related neurodegeneration; acute hypoxia; including glutamate neurotoxicity Glutamate toxicity; cerebral ischemia; dementia associated with meningitis and / or neurosis; cerebrovascular dementia; or dementia in HIV-infected patients, preferably multiple sclerosis.

  Examples of “autoimmune diseases” as used herein include rheumatoid arthritis, systemic lupus erythematosus, glomerulonephritis, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmunity Hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, ulcerative colitis, Crohn's disease, psoriasis or graft versus host A disease, preferably rheumatoid arthritis.

  Examples of “inflammatory diseases” as used herein include asthma, autoimmune diseases (including multiple sclerosis, systemic lupus erythematosus), chronic inflammation, chronic prostatitis, nephritis, hypersensitivity, inflammatory Bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, graft rejection and vasculitis.

  Inflammatory diseases are various cells such as local vasculature, immune system and injured tissues such as brain, spinal cord, synovial joint, organ system (heart, liver, kidney, lung, intestine) and soft tissue (muscle, skin) It will be appreciated that the disease involves a cascade of biochemical events including: For the purposes of the present invention, inflammation can be either acute or chronic. Inflammatory diseases of the present invention include those involved in the immune system (ie as evidenced by allergic reactions and some muscle diseases). Inflammatory diseases of the present invention further include nonimmune diseases that have an etiological source in the inflammatory process, including cancer, atherosclerosis and ischemic heart disease.

  The compounds of the invention are further provided for the prevention and / or treatment of organ failure, particularly of the heart, liver or kidney. Examples of “organ failure” as used herein include chronic or acute heart failure, cardiac hypertrophy, dilated, hypertrophic or restricted cardiomyopathy, acute myocardial infarction, post myocardial infarction, acute or chronic myocarditis, left ventricle Diastolic dysfunction, left ventricular systolic dysfunction; hypertension and nephropathy and its associated nephritis, diabetic nephropathy, endothelial dysfunction, arteriosclerosis or post-angioplasty restenosis. The invention particularly relates to the prevention and / or treatment of diabetic nephropathy.

  The compounds of the present invention further include rheumatoid arthritis, osteoarthritis, gout, chronic obstructive pulmonary disease, asthma, bronchitis, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, mucinous colitis, ulcerative Colitis, Crohn's disease, gastritis, esophagitis, eczema, dermatitis, hepatitis, nephritis, eye disease, diabetic retinopathy, diabetic macular edema, diabetic nephropathy, diabetic neuropathy, obesity, psoriasis, cancer, stroke Provided for the prevention and / or treatment of cerebrovascular disorders, ischemic disorders of organs selected from the heart, kidney, liver and brain, ischemia reperfusion injury, endotoxic shock or transplant rejection .

  The term “halogen atom” as used herein means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc., preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom.

The term “C _1-6 alkyl group” as used herein means an alkyl group that is a straight or branched chain having 1 to 6 carbon atoms. Thus, an alkyl group has 1, 2, 3, 4, 5 or 6 carbon atoms. In particular, examples of “C _1-6 alkyl group” include methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group. N-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, n-hexyl group, 1-ethyl-2-methylpropyl group 1,1,2-trimethylpropyl group, 1-ethylbutyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, Examples include 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, and 3-methylpentyl group.

As used herein, the term “C _1-6 alkoxy group” means an oxy group bonded to the “C _1-6 alkyl group” defined above. In particular, examples of “C _1-6 alkoxy group” include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n- Pentyloxy group, isopentyloxy group, sec-pentyloxy group, n-hexyloxy group, isohexyloxy group, 1,1-dimethylpropoxy group, 1,2-1 dimethylpropoxy group, 2,2-dimethylpropoxy group 2-methylbutoxy group, 1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group 2,3-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2-ethylbutoxy group, 2-methylpentyloxy , And the like 3-methyl pentyl group.

The term “(C _1-6 alkyl) amino group” as used herein means an amino group substituted with a C _1-6 alkyl group as described above.

The term “di (C _1-6 alkyl) amino group” as used herein means an amino group substituted with two C _1-6 alkyl groups as described above.

  The term “5- to 7-membered non-aromatic hydrocarbon ring group” as used herein refers to a 5- to 7-membered cycloalkyl group, a 5- to 7-membered cycloalkenyl group, and a 5- to 7-membered cycloalkadienyl. Means group. Thus, a non-aromatic hydrocarbon ring group has 5, 6 or 7 ring members. In particular, examples of the “5- to 7-membered non-aromatic hydrocarbon ring group” include a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclopentadienyl group, a cyclohexadienyl group, and the like. There are enyl and cycloheptadienyl groups.

  As used herein, the term “4-7 membered non-aromatic heterocyclic group” has no aromaticity, and the number of atoms forming the ring is 4, 5, 6 or 7, It means a heterocyclic group containing one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. In particular, examples of “4- to 7-membered non-aromatic heterocyclic group” include azetidinyl group, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, piperazinyl group, piperazinyl group, morpholinyl group, tetrahydropyranyl group, dioxanyl group, diazepanyl. And oxazepanyl group.

As used herein, the term “C _6-10 aryl group” is an aryl group composed of 6, 7, 8, 9 or 10 carbon atoms and including fused ring groups such as monocyclic or bicyclic groups Means. In particular, examples of the “C _6-10 aryl group” include a phenyl group, an indenyl group, a naphthyl group, and an azulenyl group. It should be noted that fused rings such as indane and tetrahydronaphthalene are also included in the aryl group.

  The term “5- to 6-membered heteroaryl group” as used herein has 5 to 6 atoms to form a ring, and is selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. A monocyclic heteroaryl group containing one or more heteroatoms. In particular, examples of the “5- to 6-membered heteroaryl group” include: 1) As a nitrogen-containing heteroaryl group, a pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group, tetrazolyl group, pyrazolyl group, Imidazolyl groups, etc .; 2) sulfur-containing heteroaryl groups, thienyl groups, etc .; 3) oxygen-containing heteroaryl groups, furyl groups, pyranyl groups, etc .; and 4) heteroaryl groups containing two or more different heteroatoms , Thiazolyl group, isothiazolyl group, isoxazolyl group, furazanyl group, oxazolyl group, oxadiazolyl group, pyrazolooxazolyl group, imidazothiazolyl group, furopyrrolyl group or pyridooxazinyl group.

  Next, the substituent of the compound of the present invention represented by the formula (I) will be described.

R ¹ is a halogen atom, an oxo group, an ethylenedioxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 hydroxyalkyl group, —C (O) OH, (C _1-6 alkyl) 5-7 membered non-aromatic optionally substituted independently with 1 to 4 substituents selected from the group consisting of amino groups, di (C _1-6 alkyl) amino groups and -Ra-Rb Represents a hydrocarbon ring group,
R ^a represents a single bond or —CH ₂ —;
R ^b is a 4- to 7-membered non-aromatic heterocyclic group optionally and independently substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C _1-6 alkyl group; C represents a _6-10 aryl group or a 5-6 membered heteroaryl group.

Preferably, R ¹ represents a cyclopentyl group, a cyclohexyl group, a cyclopentenyl group, a cyclohexenyl group or a cyclohexadienyl group.

Preferably, R ¹ represents a cyclohexyl group or a cyclohexenyl group, more preferably R ¹ represents a cyclohexyl group.

Preferably, R ¹ is a halogen atom, an oxo group, an ethylenedioxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 hydroxyalkyl group, —C (O) OH, (C _{1 ~ 6alkyl} ) amino group, di ( _C1-6alkyl ) amino group, and optionally substituted independently with 1 to 4 substituents selected from the group consisting of -R ^a -R ^b ,
R ^a represents a single bond or —CH ₂ —;
R ^b is a 4- to 7-membered non-aromatic heterocyclic group optionally and independently substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C _1-6 alkyl group; C represents a _6-10 aryl group or a 5-6 membered heteroaryl group.

R ¹ is preferably a halogen atom, an oxo group, an ethylenedioxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 hydroxyalkyl group, —C (O) OH and —R ^a Optionally and independently substituted with 1 to 4 substituents selected from the group consisting of —R ^b , where R ^a and R ^b are as defined above.

Preferably, R ¹ is a fluorine atom, oxo group, ethylenedioxy group, methyl group, ethyl group, t-butyl group, methoxy group, methylamino group, dimethylamino group, diethylamino group, azetidinyl group, piperidyl group, fluoro Optionally and independently with 1 to 4 substituents selected from the group consisting of piperidyl, pyrrolidinyl, methylpiperazinyl, isopropylpiperazinyl, methyldiazepanyl, morpholino, oxazepanyl Has been replaced.

Preferably, R ¹ is a halogen atom, an oxo group, an ethylenedioxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 hydroxyalkyl group, —C (O) OH, (C _{1 6} alkyl) amino group, di _{(C 1 to 6} alkyl) 5-7 membered substituted in optionally and independently with 1-4 substituents selected from the group consisting of amino groups and -Ra-Rb Represents a non-aromatic hydrocarbon ring group of
R ^a represents a single bond or —CH ₂ —;
R ^b is a 4- to 7-membered non-aromatic heterocyclic group optionally and independently substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C _1-6 alkyl group; C represents a _6-10 aryl group or a 5-6 membered heteroaryl group.

Preferably, R ¹ is a halogen atom, an oxo group, an ethylenedioxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 hydroxyalkyl group, —C (O) OH and —R ^a. -Represents a 5- to 7-membered non-aromatic hydrocarbon ring group optionally and independently substituted with 1 to 4 substituents selected from the group consisting of R ^b , wherein R ^a and R ^b are As defined.

Preferably, R ¹ is a halogen atom, an oxo group, an ethylenedioxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 hydroxyalkyl group, —C (O) OH, (C ₁ Cyclopentyl optionally and independently substituted with 1 to 4 substituents selected from the group consisting of _˜6 alkyl) amino groups, di (C _1-6 alkyl) amino groups and —R ^a —R ^b Group, cyclohexyl group, cyclopentenyl group, cyclohexenyl group or cyclohexadienyl group,
R ^a represents a single bond or —CH ₂ —;
R ^b is a 4- to 7-membered non-aromatic heterocyclic group optionally and independently substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C _1-6 alkyl group; C represents a _6-10 aryl group or a 5-6 membered heteroaryl group.

Preferably, R ¹ is a cyclopentyl group, cyclohexyl, optionally and independently substituted with 1 to 4 substituents selected from the group consisting of an ethylenedioxy group, a C _1-6 alkyl group and a morpholino group Represents a group, a cyclopentenyl group, a cyclohexenyl group or a cyclohexadienyl group.

Preferably, R ¹ is a fluorine atom, oxo group, ethylenedioxy group, methyl group, ethyl group, t-butyl group, methoxy group, methylamino group, dimethylamino group, diethylamino group, azetidinyl group, piperidyl group, fluoro Optionally and independently with 1 to 4 substituents selected from the group consisting of piperidyl, pyrrolidinyl, methylpiperazinyl, isopropylpiperazinyl, methyldiazepanyl, morpholino, oxazepanyl It represents a substituted cyclohexyl group or cyclohexenyl group.

More preferably, R ¹ is a fluorine atom, oxo group, ethylenedioxy group, methyl group, ethyl group, t-butyl group, methoxy group, methylamino group, dimethylamino group, diethylamino group, azetidinyl group, piperidyl group, 1 to 4 substituents optionally and independently selected from the group consisting of fluoropiperidyl, pyrrolidinyl, methylpiperazinyl, isopropylpiperazinyl, methyldiazepanyl, morpholino, oxazepanyl Represents a substituted cyclohexyl group.

Most preferably, R ¹ represents a cyclohexyl group optionally and independently substituted with a substituent selected from a methylpiperazinyl group, a morpholino group and an oxazepanyl group.

R ² represents a single bond or a carbonyl group. Preferably, R ² represents a single bond.

R ³ represents hydrogen, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 haloalkyl group, a di (C _1-6 alkyl) amino group, or a 4-7 membered non-aromatic heterocycle. Represents a ring group, wherein at least one ring heteroatom is a nitrogen atom optionally and independently substituted with 1 to 4 C _1-6 alkyl groups.

Preferably R ³ represents a hydroxyl group, a di (C _1-6 alkyl) amino group or a 4-7 membered non-aromatic heterocyclic group, wherein at least one ring heteroatom is 1-4. A nitrogen atom optionally and independently substituted with a number of C _1-6 alkyl groups.

Preferably, R ³ is hydrogen, a methyl group, a methoxy group, an ethoxy group, a trifluoromethyl group, a dimethylamino group, a piperidyl group, a piperazinyl group, or optionally substituted independently with a C _1-6 alkyl group. Represents a morpholino group.

Preferably, R ³ represents a dimethylamino group, piperidyl group, piperazinyl group or morpholino group optionally and independently substituted with a C _1-6 alkyl group.

R ⁴ represents hydrogen or a C _1-6 alkyl group, preferably R ⁴ is hydrogen or methyl.

  A JNK inhibitor compound of formula (I) as defined above has significant in vivo activity.

Specifically, preferred compounds according to the present invention are:

Although the structural formula of this compound may be described to represent a given isomer for convenience, all isomers of this compound that may occur structurally, such as geometric isomers, optical isomers, stereoisomers and tautomers Substances are included in the present invention and are limited to the formulas described for convenience, whether they are isolated isomers (eg, enantiomers) or mixtures of isomers (eg, racemic mixtures). There is no.

  When the compounds according to the invention are obtained in free form, they can be converted into salts or hydrates thereof by conventional methods.

  In the present specification, the “salt” according to the present invention is not limited as long as it forms a salt with the compound according to the present invention and is pharmacologically acceptable. Preferred examples of the salt include hydrohalides (eg, hydrochloride, hydrobromide, hydroiodide, etc.), inorganic acid salts (eg, sulfate, nitrate, perchlorate, phosphoric acid) Salt, carbonate, bicarbonate, etc.), organic carboxylates (eg acetate, maleate, tartrate, fumarate, citrate, etc.), organic sulfonates (eg methanesulfonate, Ethane sulfonate, benzene sulfonate, toluene sulfonate, camphor sulfonate, etc.), amino acid salt (eg, aspartate, glutamate, etc.), quaternary ammonium salt, alkali metal salt (eg, sodium salt) And alkaline earth metal salts (magnesium salts, calcium salts, etc.). Furthermore, hydrochlorides, sulfates, methanesulfonates, acetates, etc. are preferred as “pharmacologically acceptable salts” of the compounds according to the invention.

  Furthermore, when the compounds according to the invention can contain various isomers (eg geometric isomers, optical isomers, rotational isomers, tautomers etc.), conventional separation methods such as recrystallization, diastereomers, etc. It can also be purified to a single isomer by optical resolution such as salt method, enzyme resolution method, and various chromatographic methods (for example, thin layer chromatography, column chromatography, glass chromatography, etc.). However, single isomers herein include not only 100% pure isomers but also isomers that still have non-target isomers after performing conventional purification operations. Furthermore, when the compound according to the present invention is used as a raw material for pharmaceuticals, the above-mentioned single isomer may be used, and a mixture of isomers in an arbitrary ratio may be used.

  A crystalline polymorph may exist in the compound according to the present invention, a salt thereof, or a hydrate thereof, and all the polymorphic crystals are included in the present invention. Crystal morphisms may exist in a single isomer or mixture, both of which are included in the present invention.

  Furthermore, compounds that still exhibit the desired pharmacological activity after the compounds according to the invention have undergone metabolism such as in vivo oxidation and hydrolysis are also included in the present invention.

  Further included in the present invention are so-called prodrugs that yield a compound according to the present invention when subjected to metabolism such as in vivo oxidation, reduction and hydrolysis.

  The compounds according to the invention can be provided as pharmaceutical compositions. The pharmaceutical composition may additionally comprise a pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier and / or a pharmaceutically acceptable diluent. Suitable carriers and / or diluents are well known in the art and include pharmaceutical grade starch, mannitol, lactose, magnesium stearate, sodium saccharine, talc, cellulose, glucose, sucrose (or other sugar), carbonic acid There are magnesium, gelatin oil, alcohol, surfactant, emulsifier or water (preferably sterile). The composition may be a mixed formulation of the composition or a combined formulation for separate or sequential use (including administration) at the same time.

  The compounds according to the invention, their salts or their hydrates can be formulated in a conventional manner. Examples of preferred dosage forms include tablets, powders, fine granules, granules, coated tablets, capsules, syrups, lozenges, inhalants, suppositories, injections, ointments, eye ointments, eye drops, nasal drops , Ear drops, poultices, lotions, etc. In the formulation, diluents, binders, disintegrants, lubricants, colorants and flavoring agents are generally used. If necessary, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, antiseptics Additives such as agents and antioxidants can be used. Furthermore, formulation can also be achieved by combining components generally used as a raw material of the formulation by a conventional method. Examples of these ingredients include: (1) animal oils and synthetic glycerides such as soybean oil, beef tallow; (2) hydrocarbons such as liquid paraffin, squalane and solid paraffin; (3) octyldodecyl myristate and isopropyl myristate. (4) higher alcohols such as cetostearyl alcohol and behenyl alcohol; (5) silicone resin; (6) silicone oil; (7) polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid Surfactants such as esters, polyoxyethylene hydrogenated castor oil and polyoxyethylene polyoxypropylene block copolymers; (8) hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyester Water-soluble polymers such as ethylene glycol, polyvinylpyrrolidone and methylcellulose; (9) lower alcohols such as ethanol and isopropanol; (10) polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; (11) glucose and sugarcane (12) inorganic powders such as silicic anhydride, magnesium aluminum silicate and aluminum silicate; and (13) purified water.

  Among the above additives, 1) as a diluent, lactose, corn starch, sucrose, glucose, mannitol, sorbitol, microcrystalline cellulose, silicon dioxide, etc .; 2) as a binder, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, Arabic Rubber, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polypropylene glycol / polyoxyethylene block copolymer, meglumine, calcium citrate, dextrin, pectin, etc .; 3) starch, agar, gelatin as disintegrant Powder, microcrystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, calcium carbox 4) As a lubricant, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc .; 5) As a colorant, a colorant as long as its addition to the drug is permitted; 6) A flavoring agent Cocoa powder, menthol, fragrance, peppermint oil, cinnamon powder; and 7) antioxidants such as ascorbic acid and α-tocopherol that are allowed to be added to the drug can be used as antioxidants. .

  The compounds of the invention are usually calculated, for example, as free base between 1 mg and 2000 mg, preferably between 30 mg and 1000 mg, for example 10 to 250 mg of the compound of formula (I) or physiologically acceptable salts thereof. Oral doses between, or a daily dosage regimen of 0.1 mg to 100 mg, preferably between 0.1 mg and 50 mg, eg between 1 and 25 mg, eg between 1 and 25 mg (for adult patients) ) And the compound is administered 1 to 4 times per day. Suitably the compound is administered for a period of continuous therapy, for example for a week or more.

General Procedure The method for preparing the compound represented by formula (I) is described below.

  Compound (I) can be obtained by a method represented by the following reaction schemes 1 to 8 or a method equivalent thereto.

Each reference symbol in the compounds shown in Reaction Schemes 1 to 8 below has the same meaning as defined above. The compound shown in the reaction scheme includes a salt formed from the compound, and examples of the salt include the same salt as the salt of compound (I).

Wherein R ¹ , R ² and R ³ have the same meaning as above, X ¹ and X ² independently represent a halogen atom, and L ¹ is an amino protected group such as a phenylsulfonyl group or a dimethylamino group. L ³ and L ⁴ independently represent a trialkyltin group, B (OR ³² ) ₂ or SiR ³³ ₂ , where each of R ³² is independently hydrogen or C _1-6 Represents alkyl, or two R ³² together with the boron and oxygen atoms form a 5- to 7-membered ring, where the ring is optionally substituted with 1-4 C _1-6 alkyl groups Each of R ³³ represents a fluoro atom, a hydroxyl group, or a C _1-6 alkyl group.

Step 1-1
Compound (III) can be produced by coupling compound (IV) with compound (V) in the presence of a metal catalyst disclosed in WO2004 / 077876 and WO2006 / 015123. Coupling reactions include known coupling reactions; Stille reaction, Suzuki coupling, Hiyama reaction, and the like. Stille reactions are described as Still (Angew. Chem., Int. Ed, Engl. 1986, 25, 508); Mitchell (Synthesis, 1992, 803) or Littke et al. (J. Am. Chem. Soc. 2002, 124, 6343). Can be implemented according to Suzuki coupling can be performed according to Suzuki (Pure Appl. Chem. 1991, 63, 419) or Littke et al. (J. Am. Chem. Soc. 2000, 122, 4020). The Hiyama reaction can be performed as described by Hatanaka et al. (J. Org. Chem. 1988, 53, 918), Hatanaka et al. (Synlett, 1991, 845), Tamao et al. (Tetrahedron Lett. 1989, 30, 6051), or Denmark et al. (Org. Lett 2000, 2, 565, ibid, 2491).

  Compound (IV) may be commercially available or may be prepared from commercially available products by methods known to those skilled in the art.

  Compound (V) can be commercially available or can be prepared from commercially available products by methods known to those skilled in the art.

Step 1-2
Compound (II) can be produced by coupling compound (III) with compound (VI) in the presence of a metal catalyst as in Step 1-1.

Compound (VI) may be commercially available or may be prepared from commercially available products by methods known to those skilled in the art. For example, the stannane described as (VIa) can be prepared from the relevant ketone using several methods well known in the art (J. Org. Chem. 2004, 69, 9109). For example, a ketone can first be converted to an enol triflate as shown below.

In the formula, R is a halogen atom, an oxo group, an ethylenedioxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 hydroxyalkyl group, —C (O) OH, (C _{1 6} alkyl) amino group, di (C _1-6 alkyl) amino group or —R ^a —R ^b , R ^a represents ^a single bond or —CH ₂ —, R ^b represents a halogen atom and C _1-6 4-7 membered non-aromatic heterocyclic group, C _6-10 aryl group or 5-7 member optionally and independently substituted with 1 to 4 substituents selected from the group consisting of alkyl groups Represents a heteroaryl group.

As the base, NaH (Org. Biomol. Chem. 2006, 4 (3), 410), (CH ₃ Si) ₂ NLi, (CH ₃ Si) ₂ NK (J. Org. Chem. 2003, 68, 6905) or the _i-Pr 2 NLi can be used. A suitable palladium catalyst for the second step is tetrakis (triphenylphosphine) palladium (0) Pd (PPh ₃ ) ₄ . An alternative method (J. Org. Chem. 2004, 69, 220) starts from a commercially available ketone (VII) with the relevant vinyllithium derivative as an intermediate.

Boronic esters described as (VIb) can also be obtained from the related ketone (VII) by methods well known in the art as shown below (J. Med. Chem. 2006, 49, 3719-3742 or WO 2005). / 005422) can be manufactured using:

As the base, (CH ₃ Si) ₂ NLi or i-Pr ₂ NLi can be used. Suitable palladium catalysts for the reaction of triflate (VIII) with bis (pinacolato) diboron include 1,1′-bis (diphenylphosphino) ferrocene PdCl ₂ ^. There are palladium (II) chloride complexes with dppf or palladium (II) chloride complexes with triphenylphosphine PdCl ₂ (PPh ₃ ) ₂ .

Similar chemistry used for the preparation of stannane described as (VIa) can be used to convert ketone (VII) to the related silane described as (VIc) (J. Am. Chem. Soc. 1987, 109, 7838).

Compound (II) can also be prepared by the Heck reaction as shown below.

Various regioisomers of (IIa) can be formed depending on the reaction conditions. The reactions are X ¹ = I (Synlett 2002, 12, 2045), X ¹ = Br (Org. Lett. 1999, ¹ , 709), X ¹ = Cl (Synlett 2000, 11, 1589), and the elements Pd, chloro With various palladium catalysts including [4- (diphenylphosphino-κP) benzamide] (η3-2-propenyl) palladium, tris (dibenzylideneacetone) dipalladium, palladium diacetate and the like. The reaction can be carried out in the presence of a phosphine such as butyl bis (tricyclo [3.3.1.13,7] dec-1-yl) phosphine, tricyclohexylphosphine, or triphenylphosphine.

Step 1-3
Conditions of removal of L ¹ groups is a function of the characteristics of the group ^{L 1.} For example, when L ¹ is a phenylsulfonyl group, the compound of formula (I) is treated by treating the compound of formula (II) under basic conditions, for example using sodium hydroxide in water / ethanol. Can be generated. Specifically, the following examples are described in detail.

If desired, modification of R ¹ , R ² or R ³ may be performed before or after each step. For example, compound (IIa) containing an unsaturated ring can be reduced to compound (IIb) containing a saturated ring. Reduction can be achieved by using hydrogen gas over a catalyst such as palladium, palladium hydroxide, platinum or rhodium.

In particular, by reducing the cyclohexenyl derivative (IIa), a mixture of cis- and trans- (IIb) can be prepared as shown below.

Such mixtures can be separated, if necessary, using chromatographic methods well known in the art. Alternatively, cis isomers such as cis- (IIb) can be obtained using the free radical method developed by Bertrand et al. (J. Org. Chem. 2006, 71, 7288), such as trans- (IIb) The thermodynamically more stable trans-isomer can be converted.

Compound (II) may undergo one or more further reactions to provide another compound (II). For example, the compound may undergo hydrolysis, reductive amination, reduction, oxidation, elimination, substitution and / or addition reactions. Particularly for reductive amination, the following examples are detailed.

Furthermore, if desired, the order of step 1-1 and step 1-2 can be interchanged as follows. Alternatively, the compound of formula (II) is
a) reaction of a compound of formula (IX) with stannane (Va) in the presence of a palladium catalyst or b) reaction of a compound of formula (IX) with a boronic acid or ester (Vb) in the presence of a suitable palladium catalyst Or c) reaction of a compound of formula (IX) with silane (Vc) in the presence of a palladium catalyst.

(Where all symbols in the scheme have the same meaning as above)
Can be prepared.

Suitable catalysts for the purposes of the present invention include (PPh ₃ ) ₂ PdCl ₂ or (PPh ₃ ) ₄ Pd, Pd (OAc) ₂ , [PdCl (η ³ -C ₃ H ₅ ] ₂ , Pd ₂ (dba) ₃ (dba = dibenzylideneacetone), Pd / P (t-Bu) ₃ .

  The reactions listed as option a) are Still (Angew. Chem., Int. Ed, Engl. 1986, 25, 508); Mitchell (Synthesis, 1992, 803) or Littke et al. (J. Am. Chem. Soc. 2002). , 124, 6343) will be understood to be a Stille reaction.

  The reaction listed as option b) is a Suzuki reaction which can be carried out according to Suzuki (Pure Appl. Chem. 1991, 63, 419) or Littke et al. (J. Am. Chem. Soc. 2000, 122, 4020). .

  The reactions listed as option c) are: Hatanaka et al. (J. Org. Chem. 1988, 53, 918), Hatanaka et al. (Synlett, 1991, 845), Tamao et al. (Tetrahedron Lett. 1989, 30, 6051), or Denmark. (Org. Lett. 2000, 2, 565, ibid, 2491) will be understood to be a Hiyama reaction which can be carried out.

Alternatively, a thiazole group can be introduced stepwise at the C (3) position of the compound. Scheme 2 shows a method by which thiazol-2-yl group can be formed to obtain compound (III). An important intermediate for this purpose is thioamide (XIII) synthesized as shown in Scheme 2a.

Step 2-1.
The mixed anhydride (R ¹¹ = alkyl) is obtained from the relevant carboxylic acid (X) using standard procedures known to those skilled in the art. The preparation of related acids and amides was disclosed in WO2003082868.

Step 2-2
Amides (XII) can be readily synthesized from the related mixed anhydrides (XI) using standard methods by reacting compound (XI) with ammonia hydroxide or ammonium hydroxide.

Step 2-3
Thioamide (XIII) can be readily prepared from amide (XII) using methods known in the art, such as reacting (XII) with a Lawson reagent.

Step 2-4
To prepare thiazole (III-i), amide (XIII) was converted to aldehyde (XIV) with Thompson et al., Bioorg. Med. Chem. Lett. React as indicated in 1994, 4, 2441.

Step 2-5
Thiazole (III-ii) can be obtained by condensing thioamide (XIII) with α-haloketone (XV) (Schwarz Org. Synth. 1955, III, 332; Gu et al. Bioorg. Med. Chem. Lett 1999, 9, 569).

Step 2-6
Amidine (XVI) can be prepared from thioamide (XIII) by reaction with dimethylformamide dimethyl acetal Me ₂ CH (OMe) ₂ (Thompson et al. Bioorg. Med. Chem. Lett. 1994, 4, 2441).

Step 2-7
The alkylcarbonyl group R ¹⁴ C (O) — can be converted from amidine (XVI) to α-haloketone R ¹⁴ C (O) CH ₂ Y ¹ (XVII) by methods well known in the art (Thompson et al. Bioorg. Med. Chem. Lett. 1994, 4, 2441) can be introduced into the α-position of the sulfur atom.

Alternatively, thioamide (XIII) can be formed from nitrile (XVIII), the preparation of which was disclosed in WO2004101565 (Scheme 3).

Step 3-1.
Conversion of nitrile (XVIII) to thioamide (XIII) can be achieved under various conditions. For example, thioamide (XIII) is
H ₂ S under basic conditions (Bhattacharya et al. J. Chem. Soc., Perkin Trans. I 1995, 1543; Krawczyk et al. J. Med. Chem. 1995, 38, 4115)
Thioacetamide under acidic conditions (Gu et al. Bioorg. Med. Chem. Lett. 1999, 9, 569)
-Sodium bisulfite and magnesium chloride in dimethylformamide (DMF) (Manaka and Sato Synth. Commun. 2005, 35, 761)
・ (Me ₃ Si) ₂ S / MeONa system (Lin et al. Synthesis 1992, 1219; Qiao et al. Org. Lett. 2001, 3, 3655)
Form using.

Generation of a thiazolyl group with deprotected 7-azaindole C (3) protects compound (XXIII) as shown below and in more detail in Scheme 4 to provide compound (III) To make.

Compound (III) can then be converted to (II) and (I) as described above in Scheme 1.

Step 4-1
Haloketone (XXI) can be synthesized from commercially available (XIX) using the method disclosed in WO2006015123.

Step 4-2
The thiazole derivative (XXIII-i) is formed by reacting the haloketone (XXI) with the thioamide (XXII). The reaction was performed using R ² -R ³ = NH ₂ (Hayashi et al. Heterocycles 1999, 51, 1233; Bansal et al. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2000, 39 ^{, 357), R 2 -R 3} = NH- aryl (Di Fabio and Pentassuglia Synth. Commun . 1998,28,51), R 2 -R 3 = ( substituted) alkyl (Zawistoski J. Heterocycl. Chem. 1990,27 519) and R ² -R ³ = aryl (Baldwin et al. J. Org. Chem. 2001, 66, 2588).

Step 4-3
Compound (III-i) is made by protecting compound (XXIII) with an appropriate protecting group using methods well known in the art. Preferred protecting groups include phenylsulfonyl, toluenesulfonyl and SEM.

Compound (XXIII) can be converted directly to (I) as shown below and using the conditions shown in Step 1-2, but such conversion usually results in low overall yields.

By applying the method developed by Saleh (Nucleosides, Nucleotides Nucleic Acids 2002, 21, 401) for indole analogs, thiazol-5-yl derivatives can be prepared as shown in Scheme 5.

Step 5-1
Compound (XXIV) is obtained from the related bromoketone (XXI) by reacting it with hexamethylenetetramine, followed by Heterocycles 2002, 56 (1-2), 519 and J. Org. Pharm. Pharmacol. Synthesized by acidic workup as described in 2002, 54, 147. Alternative methods for obtaining indole analogs of (XXIV) are also known (Synthesis 2006, 1, 49; J. Am. Chem. Soc. 2004, 126, 12888; Org. Lett. 2000, 2, 3185; ibid 2000, 2, 2121).

Step 5-2
α-aminoketone (XXIV) and isothiocyanate R ¹⁴ NCS (R ¹⁴ = alkyl, heterocyclyl) are reacted as taught in Saleh (Nucleosides, Nucleotides Nucleic Acids 2002, 21, 401) to give compound (XXIII-ii) Form.

Alternatively, aminoketone (XIV) can be reacted with R ³ —R ² —C (S) SCH ₂ COOH as shown in Scheme 6.

Step 6-1
This conversion is described in J. Org. Am. Chem. Soc. It can be carried out according to the method described in 2004, 126, 12897.

If desired, the order of the steps can be interchanged.

Here, all symbols in the scheme have the same meaning as described above. Compound (I) can also be prepared via compound (IX). The preparation of compound (IX) follows the general method disclosed in WO2003 / 082869 and WO2004 / 078756 starting from 5-halo-7-azaindole (XIX). Conversion of compound (XIX) to compound (XXV) follows the method described in Step 1-2. Compound (IX) is obtained by introducing the L ¹ group into compound (XXVI). However, ^one skilled in the art will appreciate that the actual synthetic sequence for preparing compound (IX) will depend on the type of protecting group L ¹ used. In particular, when L ¹ is a silyl group, the introduction of L ¹ can occur before the introduction of X ² as shown below.

The synthetic scheme from compound (IX) to compound (II) can be altered by reversing the reactive functional groups as shown in Scheme 8.

In the formula, all symbols in the scheme have the same meaning as described above.

Step 8-1
The synthesis of (XXVIII) can be performed using methods known in the art. For example, the preparation of R ¹ = substituted phenyl, L ¹ = t-butyldimethylsilyl, L ³ = SnBu ₃ and R ¹ = substituted phenyl, L ¹ = phenylsulfonyl, L ³ = -B (OCMe ₂ ) ₂ is described in WO2004078756 It is disclosed.

Step 8-2
The coupling reaction of halide (XXVIII) with stannane (XXIX-a) or borane (XXIX-b) or silane (XXIX-c) is carried out under the conditions discussed in Scheme 1.

Here, all symbols in the scheme have the same meaning as described above.

Step 9-1
Compound (II) can be prepared by reacting compound (XXX) with compound (XXXI).

A method for introducing stannane (—SnBu ₃ ) and silane (—SiMe ₃ ) moieties into 7-azaindole-based C (5) was disclosed in WO 2004/078757. Boronates and boronic acids similar to (IX) were also disclosed in WO2006 / 015123 and WO2005 / 028475.

Step 9-2
This step can be performed according to step 1-3.

EXAMPLES The present invention will be described in more detail with reference to examples, but the scope of the present invention is not considered to be limited thereto.

Synthetic Method of Synthesis of Compounds of the Invention 7-General Procedure A for Deprotection of Azaindole A
Procedure A

7-azaindole (II) (1 mmol) was dissolved in EtOH (10 mL). 10% NaOH (5 mL) was added and the reaction was heated to 80 ° C. to reflux temperature for 30-40 minutes. Cool and add saturated NaHCO ₃ solution (10 mL). It was then extracted with ethyl acetate (3 × 20 mL) and the combined organic extracts were dried over MgSO ₄ and concentrated. By silica gel chromatography (SGC) using an appropriate solvent as eluent, or by preparative TLC (PTLC) using an appropriate solvent as eluent, or water-acetonitrile (0.1% AcOH) (eluent) The crude product was purified by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using a gradient; flow rate 80 mL / min).

  In compound (II) containing an ester functional group, the crude reaction mixture was concentrated under reduced pressure to remove EtOH and neutralized by dropwise addition of glacial acetic acid to precipitate compound (I). The precipitate was filtered off, dried in vacuo and used for further conversion without further purification.

Procedure B

Concentrated aqueous HCl (1 mL) was added to a solution of silyl protected azaindole (II) (0.28-0.9 mmol) in methanol (10 mL) and the reaction mixture was stirred at room temperature for 15-30 min. The mixture was then added to saturated aqueous NaHCO ₃ (50 mL) and extracted with AcOEt (2 × 40 mL). The combined organic portions were dried (MgSO ₄ ), concentrated and purified by trituration with Et ₂ O (5 mL) to give 7-azaindole (I) as a white powder (50-95%).

General procedure for the formation of amides using 7-azaindole containing carboxylic acid functionality

In the formula, R ¹ has the same meaning as described above, and R and R ′ independently represent a hydrogen atom, a C1-6 alkyl group, or R and R ′ are bonded nitrogen. Together with the atoms form a 4- to 8-membered ring optionally substituted with a halogen atom or a C1-6 alkyl group.

To a solution of the crude acid (I-i) (0.10 mmol) in DMF (1-2 mL) was added a tertiary amine such as amine R′RNH or its hydrochloride (0.74 mmol), triethylamine or diisopropylethylamine (0. 26 mmol; 0.52 mmol when using R′RNH hydrochloride), and (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP; 130 mg, 0.30 mmol). The reaction mixture was stirred for 2 hours to 3 days, diluted with AcOEt (65 mL) and washed with saturated aqueous NaHCO ₃ (2 × 30 mL). The organic layer was dried over MgSO ₄ , concentrated and LCMS (column LUNA 10μ C18 (2) 00G-4253- using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. The residue was purified by V0 250 x 50 mm) to give amide (I-ii) as a solid. Alternatively, without workup, the crude reaction mixture is directly purified by LCMS using the above conditions. Yield 10-60%.

General procedure for hydrogenation of 7-azaindoles containing C (5) partially unsaturated rings

In the formula, R ² has the same meaning as described above, R ^1a represents a 5- to 7-membered unsaturated hydrocarbon ring, and R ^1b represents a 5- to 7-membered saturated hydrocarbon ring.

It dissolved in the compound (II-a) (1mmol) in a suitable solvent (a mixture of MeOH and _CH 2 Cl ₂ or ethyl acetate in order to improve the MeOH or solubility) (10 to 30 mL). Pd (OH) ₂ (0.1-0.3 mmol) (20% on C, wet, Degussa type) or Pd / C (0.25-0.50 mmol) (10% on C, wet Degussa type E101) Was added at once. The reaction was stirred for 1-7 days under hydrogen. The reaction mixture was filtered through a small pad of celite and washed with copious amounts of MeOH. Removal of the solvent gave the product (IIb) which was then advanced as a crude product.

General Procedure Procedure A for Reductive Amination Using 7-Azaindole Containing Amine and Keto Functional Groups

In the formula, R ² , R ³ , R and R ′ have the same meaning as described above.

Ketone (IIb-i) (1 mmol) was added to a solution of secondary amine R′RNH hydrochloride (6 mmol) in dry MeOH (10 ml) under nitrogen over 5 min at room temperature (RT) and then the mixture was added at room temperature for 5 min. Stir for minutes. When the free amine was used, the hydrochloride salt was prepared in situ by dropwise addition of a 1.25M solution of HCl in MeOH (2 mmol) and stirring at room temperature for 5 minutes. Solid NaBH ₃ CN (2 mmol) was added as a solid all at once at room temperature or as a MeOH (4 mL) solution at −20 ° C. The reaction was then stirred overnight at room temperature. Saturated NaHCO ₃ solution (30 ml) was added and the reaction mixture was extracted with ethyl acetate (4 × 35 ml). The combined organic extracts were dried over MgSO ₄ and concentrated. By silica gel chromatography (SGC) using an appropriate solvent as eluent, or by preparative TLC (PTLC) using an appropriate solvent as eluent, or water-acetonitrile (0.1% AcOH) (eluent) The crude product was purified by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using a gradient; flow rate 80 mL / min) to obtain trans- (IIb) and cis- (IIb) Got.

Procedure B

Acetic acid (1 mmol) is added to a solution of ketone (IIb-i) (0.5 mmol) and amine RR′NH (1.5 mmol) in 1,2-dichloroethane (4.4 mL) and the reaction mixture is stirred at room temperature for 10 minutes. did. Solid triacetoxyborohydride (210 mg, 1 mmol) was then added and the reaction mixture was stirred overnight. The solution was then poured into saturated aqueous NaHCO ₃ (37 mL) and extracted with AcOEt (3 × 60 mL). The combined organic extracts are dried over MgSO ₄ , concentrated and purified by silica gel chromatography (SGC) using a suitable solvent as eluent or by preparative TLC (PTLC) using a suitable solvent as eluent. Or purified by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent and trans -(IIb) and cis- (IIb) were obtained.

General Procedure Procedure A for the Suzuki Reaction

In the formula, each symbol has the same meaning as described above.

Bromide (III) (1 mmol), boronic acid or boronic acid pinacol ester R ¹ -B (OR ³² ) ₂ (2 mmol), LiCl (3 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (0.1 mmol) were added to EtOH ( 20 mL) and toluene (20 mL). Then 1.0 M Na ₂ CO ₃ solution (20-25 mL) was added and the reaction was heated to 105-110 ° C. for 8 hours. The reaction mixture was cooled. Poured into water (30 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic extracts were dried over MgSO ₄ and concentrated. Product by silica gel chromatography (SGC) using hexane / ethyl acetate (gradient elution 0% to 100% ethyl acetate) as eluent or by preparative TLC (PTLC) using an appropriate solvent system as eluent (IIa) was isolated.

Essentially the same protocol can be used to convert (XXIII) to (Ia).

The crude extract of product (Ia) was then purified by LCMS (column LUNA 10μ C18 (2) 00G-4253- using eluent (gradient; flow rate 80 mL / min) with water-acetonitrile (0.1% AcOH). V0 250 x 50 mm).

Procedure B

In the formula, each symbol has the same meaning as described above.

Halide (IV) [10 mmol; Preparation of (IV-a) (X ¹ = Br, X ² = I, L ¹ = SO ₂ Ph) disclosed in WO 2004/078756], boronic acid or Boronic acid pinacol ester (Vb) (11 mmol), LiCl (30 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (0.5 mmol) and 1.0 M Na ₂ CO ₃ solution (25 mL) in EtOH (25 mL) and toluene ( 25 mL) The mixture was heated at 100 ° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with water (35 mL) and extracted with ethyl acetate (4 × 40 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated. The product (III) was isolated by crystallization and / or by silica gel chromatography (SGC) using an appropriate solvent system as eluent. Yield 33-80%.

Procedure A using the general procedure for Stille reaction (IV-a)

(IV-a) (10 mmol; the preparation disclosed in WO 2004/078756), trialkylstannane (V) (10 mmol), tri-o-tolylphosphine (380 mg, 1.25 mmol) and bis ( A stirred solution of acetonitrile) dichloropalladium (II) (160 mg, 0.62 mmol) in toluene (32 mL) was refluxed for 6 hours (bath temperature 110 ° C.). The reaction mixture was then cooled, diluted with AcOEt (210 mL) and washed with saturated aqueous NaHCO ₃ (2 × 50 mL). The organic layer was dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel chromatography (SGC) using an appropriate solvent system as the eluent. Yield 44%.

Procedure B using (IX)

To a stirred solution of (IX) (0.5 mmol) in toluene (2.3 mL), dichlorobis (acetonitrile) palladium (II) (12 mg, 0.05 mmol), tri-o-tolylphosphine (28 mg, 0.09 mmol) and related Stannane (V) (0.6 mmol) was added. The reaction was heated to reflux (bath temperature 110 ° C.) and the reaction was monitored by TLC. When starting material was no longer present (2-6 h), the reaction mixture was poured into saturated aqueous NaHCO ₃ (60 mL) and extracted with AcOEt (2 × 60 mL). The combined organic solution was dried (MgSO ₄ ) and concentrated to give an oil which was used as SGC and eluent from CH ₂ Cl ₂ : hexane: AcOEt (CH ₂ Cl ₂ : hexane: AcOEt = 1: 1: 0. 9: 9: 2, v / v gradient) to give protected 3-thiazolyl 7-azaindole (II). Yield 25-80%.

General procedure for the protection of (XXIII)

(XXIII) in _CH 2 _Cl 2 _(53mL) stirred solution of _{(10mmol), n-Bu 4} NHSO 4 (71mg~500mg, 0.21mmol~1.47mmol) and 50% NaOH aqueous solution (1.4 mL) was added . PhSO ₂ Cl (1.8 mL, 14 mmol) was then added dropwise and the reaction was stirred at room temperature for 1.5 hours. The mixture was then diluted with EtOAc (290 mL) and acetone (14 mL), washed with brine (2 × 70 mL) and concentrated to give crude (III). This product can be purified by SGC using an appropriate solvent system as the eluent, or recrystallized from CH ₂ Cl ₂ / hexane to give pure (III). Further product was obtained from the mother liquor by purification by SGC. Total yield of (III) 40-60%. The same procedure can be applied to the protection of (XXVI) to give (IX).

General procedure for the synthesis of enol triflate.

In the formula, R has the same meaning as described above.

To a THF (35 mL) solution of ketone (VII) (10 mmol) cooled to −78 ° C., a THF 1.0M solution of LiHMDS (12 mL, 12 mmol) was added dropwise. Stirring was continued at -78 ° C for 1 hour. N-phenylbis (trifluoromethanesulfonimide) (3.93 g, 11 mmol) was added in one portion and stirring was continued at −78 ° C. for 1 hour and then at room temperature for 19.5 hours. The solvent was evaporated and the crude product was purified by column chromatography on alumina (neutral, grade 1) using hexane: ethyl acetate = 7: 1 (v / v) as eluent. Instead, the product was isolated by SGC using ethyl acetate: hexane: Et ₃ N = 39: 60: 1 (v / v / v) (gradient elution starting at 19: 80: 1) as the eluent. , Triflate (VIII) can be obtained. Yield 62-84%.

General procedure for the synthesis of boronic acid pinacol esters.

In the formula, R has the same meaning as described above.

  Triflate (VIII) (10 mmol), bis (pinacolatodiboron) (3.80 g, 15 mmol), potassium acetate (2.94 g, 30 mmol) and dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) A mixture of dichloromethane adduct (0.41 g, 0.5 mmol) in DMF (43 mL) was stirred at 85 ° C. for 6-17 hours to obtain a homogeneous black solution. The reaction mixture was concentrated and diluted with ethyl acetate. The solid was filtered off and the filtrate was concentrated. The residue was purified by SGC using ethyl acetate: hexane = 1: 1 (v / v) (gradient eluent) as eluent to give compound (VI-b). Yield 47-67%.

5-Cyclopent-1-enyl-3- [2- (1-methyl-piperidin-4-yl) -thiazol-4-yl] -1H-pyrrolo [2,3-b] pyridine (I-1)

Compound (IIa-1) (213 mg, 0.42 mmol) in EtOH (4 mL) and 10% aqueous NaOH (2 mL) was refluxed for 30 min as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product (I-1) (xxmg, xx%) was a pale yellow solid and was sufficiently pure. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.94-2.28 (m, 8H), 2.37 (s, 3H), 2.57-2.65 (m, 2H), 2.83-2 .90 (m, 2H), 3.02 (br d, J = 11.6 Hz, 2H), 3.10 (tt, J = 3.9, 11.6 Hz, 1H), 6.70 (quintet) , J = 2.1 Hz, 1H), 7.28 (s, 1H), 7.85 (d, J = 2.3 Hz, 1H), 8.39 (d, J = 1.9 Hz, 1H), 8 .55 (d, J = 1.9 Hz, 1H), 10.27 (s, 1H). MS (CI) m / z 365 (MH ^<+> ).

4- (5-Cyclopentenyl-1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole-2-carboxylic acid (I-2)

Compound (IIa-39) (372 mg, 0.22 mmol) in EtOH (4 mL) and 10% aqueous NaOH (2 mL) was refluxed for 1 h as described in General Procedure A for 7-azaindole deprotection. By deprotection. The reaction mixture was concentrated to about 2 mL and neutralized by adding AcOH dropwise. The precipitate was filtered off to give crude product (I-2) (256 mg, crude yield> 100%) as a yellow powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.23 (quintet, J = 7.5 Hz, 2H), 2.71 to 2.79 (m, 2H), 2.99 to 3.07 ( m, 2H), 6.58-6.62 (m, 1H), 8.04 (s, 1H), 8.23 (s, 1H), 8.66 (d, J = 2.0 Hz, 1H) 8.67 (d, J = 2.0 Hz, 1H).

[4- (5-Cyclopent-1-enyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -thiazol-2-yl] -morpholin-4-yl-methanone (I-3)

Compound (I-2) (25 mg, 75 μmol or less), triethylamine (20 mg, 0.20 mmol), morpholine (50 mg, 0.57 mmol) and BOP (100 mg, 0.23 mmol) in DMF (1 mL) form an amide. Was converted to (I-3). The crude product obtained by work-up by extraction (36 mg) was purified by LCMS (column LUNA 10 μ C18 (2) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. 00G-4253-V0 250 × 50 mm) to give (I-3) (18 mg, 47 μmol, 59%) as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.21 (quintet, J = 7.5 Hz, 2H), 2.59-2.66 (m, 2H), 2.81-2.88 (m, 2H), 3.85 to 3.95 (m, 6H), 4.66 to 4.74 (m, 2H), 6.26 to 6.29 (m, 1H), 7.59 (s, 1H) 7.80 (s, 1H), 8.37 (d, J = 1.8 Hz, 1H), 8.58 (d, J = 1.8 Hz, 1H), 10.02 (brs, 1H). MS (CI) m / z 381 (MH ^<+> ).

[4- (5-Cyclopent-1-enyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -thiazol-2-yl] -piperidin-1-yl-methanone (I-4)

Compound (I-2) (100 mg, 0.30 mmol or less), triethylamine (50 mg, 0.49 mmol), piperidine (80 mg, 0.94 mmol) and BOP (150 mg, 0.34 mmol) in DMF (2 mL) Converted to (I-4) by stirring for hours and following the general procedure for amide formation. Purify the crude reaction mixture by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent (I-4) (57 mg, 0.15 mmol, 50%) was obtained as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.73-1.84 (m, 6H), 2.12 (quintet, J = 7.5 Hz, 2H), 2.59-2.66 (m, 2H), 2.81 to 2.89 (m, 2H), 3.76 to 3.86 (m, 2H), 4.40 to 4.52 (m, 2H), 6.27 (quintage, J = 2.2 Hz, 1H), 7.55 (s, 1H), 7.82 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 1.9 Hz, 1H), 8. 59 (d, J = 1.9 Hz, 1H), 10.14 (s, 1H). MS (CI) m / z 379 (MH ^<+> ).

[4- (5-Cyclopent-1-enyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -thiazol-2-yl]-(4-methyl-piperazin-1-yl) -methanone ( I-5)

Compound (I-2) (100 mg, 0.30 mmol or less), triethylamine (50 mg, 0.49 mmol), N-methylpiperazine (80 mg, 0.80 mmol) and BOP (150 mg, 0.34 mmol) in DMF (2 mL) Was converted to (I-5) by stirring for 18 hours and following the general procedure for amide formation. Purify the crude reaction mixture by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) as eluent (gradient; flow rate 80 mL / min). To give (I-5) (52 mg, 0.13 mmol, 44%) as a yellow powder. ¹ H NMR (400 MHz, D-6 DMSO) δ 2.02 (quintet, J = 7.5 Hz, 2H), 2.42 to 2.57 (m, 7H), 2.76 to 2.83 ( m, 2H), 2.92 to 3.00 (m, 2H), 3.68 to 3.75 (m, 2H), 4.41 to 4.49 (m, 2H), 6.35 (quintet) Line, J = 2.2 Hz, 1H), 8.08 (d, J = 2.6 Hz, 1H), 8.19 (s, 1H), 8.40 (d, J = 1.9 Hz, 1H), 8.52 (d, J = 1.9 Hz, 1H), 12.03 (s, 1H). MS (CI) m / z 394 (MH ^<+> ).

4- (5-Cyclohexyl-1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole-2-carboxylic acid (I-6)

The crude compound (IIb-42) (600 mg, 1.12 mmol or less) in EtOH (7 mL) and 10% aqueous NaOH (3.5 mL) was added as described in General Procedure A for 7-azaindole deprotection. Deprotected by refluxing for 1 hour. The reaction mixture was concentrated to about 4 mL and neutralized by adding AcOH dropwise. The precipitate was filtered off to obtain a crude product (I-6) (370 mg, crude yield 100%) as a powder. ¹ H NMR (400 MHz, D-6 DMSO) δ 1.23-1.50 (m, 4H), 1.52-1.65 (m, 2H), 1.69-1.89 (m, 4H) 2.65 to 2.69 (m, 1H), 7.72 (s, 1H), 7.93 (s, 1H), 8.15 (d, J = 2.1 Hz, 1H), 8.29 (D, J = 2.1 Hz, 1H), 11.68 (br s, 1H).

[4- (5-Cyclohexyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -thiazol-2-yl] -piperidin-1-yl-methanone (I-7)

Compound (I-6) (75 mg, 0.23 mmol or less), diisopropylethylamine (80 mg, 0.62 mmol), piperidine (85 mg, 1.00 mmol) and BOP (150 mg, 0.34 mmol) in DMF (1 mL) Converted to (I-7) by stirring for 24 hours and following the general procedure for amide formation. Purify the crude reaction mixture by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent (I-7) (19 mg, 49 μmol, 21%) was obtained as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.26 to 1.40 (m, 1H), 1.42 to 1.61 (m, 4H), 1.80 to 2.05 (m, 6H), 2 .67-2.77 (m, 1H), 3.83-3.95 (m, 6H), 4.64-4.75 (m, 2H), 7.54 (s, 1H), 7.82 (S, J = 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 10.33 (br s, 1H). MS (CI) m / z 395 (MH ^<+> ).

[4- (5-Cyclohexyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -thiazol-2-yl] -morpholin-4-yl-methanone (I-8)

Compound (I-6) (75 mg, 0.23 mmol or less), diisopropylethylamine (80 mg, 0.62 mmol), morpholine (87 mg, 1.00 mmol) and BOP (150 mg, 0.34 mmol) in DMF (1 mL) Conversion to (I-8) by stirring for 24 hours and following the general procedure for amide formation. Purify the crude reaction mixture by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent (I-8) (46 mg, 116 μmol, 50%) was obtained as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.25 to 1.39 (m, 1H), 1.42 to 1.63 (m, 4H), 1.72 to 1.88 (m, 7H), 1 .89 to 2.04 (m, 4H), 2.67 to 2.76 (m, 1H), 3.78 to 3.86 (m, 2H), 4.43 to 4.51 (m, 2H) 7.55 (s, 1H), 7.82 (s, J = 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H) 10.57 (brs, 1H). MS (CI) m / z 397 (MH ^<+> ).

4- [5-Cyclohexyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -thiazole-2-carboxylic acid dimethylamide (I-9)

Compound (I-6) (75 mg, 0.23 mmol or less), diisopropylethylamine (160 mg, 1.24 mmol), dimethylamine hydrochloride (82 mg, 1.00 mmol) and BOP (150 mg, 0.34 mmol) in DMF (1 mL) ) Was converted to (I-8) by stirring for 24 hours and following the general procedure for amide formation. Purify the crude reaction mixture by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent (I-9) (31 mg, 87 μmol, 38%) was obtained as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.29-1.39 (m, 1H), 1.42-1.60 (m, 4H), 1.79-1.87 (m, 1H), 1 .89 to 1.96 (m, 2H), 1.97 to 2.04 (m, 2H), 2.66 to 2.76 (m, 1H), 3.25 (s, 3H), 3.80 (S, 3H), 7.56 (s, 1H), 7.79 (d, J = 1.9 Hz, 1H), 8.26 (d, J = 2.1 Hz, 1H), 8.27 (d , J = 2.1 Hz, 1H), 9.22 (br s, 1H). MS (CI) m / z 355 (MH ^<+> ).

[4- (5-cyclohexyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -thiazol-2-yl]-(4-methyl-piperazin-1-yl) -methanone (I-10)

Compound (I-6) (75 mg, 0.23 mmol or less), diisopropylethylamine (80 mg, 0.62 mmol), N-methylpiperidine (100 mg, 1.00 mmol) and BOP (150 mg, 0.34 mmol) in DMF (1 mL) ) Was converted to (I-8) by stirring for 24 hours and following the general procedure for amide formation. Purify the crude reaction mixture by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent (I-10) (17 mg, 42 μmol, 18%) was obtained as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.20 to 1.31 (m, 1H), 1.33 to 1.54 (m, 4H), 1.71 to 1.80 (m, 1H), 1 81 to 1.96 (m, 4H), 2.31 (s, 3H), 2.47 to 2.59 (m, 4H), 2.59 to 2.69 (m, 1H), 3.79 To 3.88 (m, 2H), 4.51 to 4.61 (m, 2H), 7.47 (s, 1H), 7.72 (s, 1H), 8.19 (d, J = 1) .9 Hz, 1 H), 8.35 (d, J = 1.9 Hz, 1 H). MS (CI) m / z 410 (MH ^<+> ).

5-cyclohexyl-3- [2- (1-methyl-piperidin-4-yl) -thiazol-4-yl] -1H-pyrrolo [2,3-b] pyridine (I-11)

EtOH (2 ml), toluene (2 ml) and bromide (III-h) of _Na 2 CO ₃ solution (1.0 ml) of 1.0M (291mg, 0.56mmol), cyclohex-1-Eniruboron acid (90 mg, 0.71 mmol), lithium chloride (70 mg, 1.65 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (30 mg, 43 μmol) were reacted for 1 hour using the general procedure A for the Suzuki reaction. The two phase mixture was then cooled, diluted with AcOEt (100 mL) and washed with NaHCO ₃ (3 × 25 mL). The organic layer was then dried over MgSO ₄ and concentrated to give crude (IIa-40) (218 mg). The product was hydrogenated using the general procedure for hydrogenation of 7-azaindole using 20% Pd (OH) ₂ / C (Degussa form, 40 mg) in MeOH (5 mL) over 2 days. The reaction mixture was then filtered through celite and concentrated to give the crude reduction product (IIb-11) (115 mg) as an oil. By refluxing crude compound (IIb-11) (115 mg) in EtOH (2 mL) and 10% aqueous NaOH (1 mL) for 1 h as described in General Procedure A for 7-azaindole deprotection. Deprotected. The crude product was then purified by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. (I-11) was purified to give (I-11) (4 mg, 11 μmol, 2%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.29 to 1.39 (m, 1H), 1.41 to 1.61 (m, 4H), 1.78 to 1.86 (m, 1H), 1 .87 to 2.01 (m, 4H), 2.09 to 2.20 (m, 2H), 2.28 to 2.36 (m, 2H), 2.43 to 2.56 (m, 5H) 2.65 to 2.75 (m, 1H), 3.16 to 3.27 (m, 3H), 7.27 (s, 1H), 7.80 (m, 1H), 8.15 (d , J = 1.8 Hz, 1H), 8.24 (d, J = 1.8 Hz, 1H), 10.51 (s, 1H). MS (CI) m / z 381 (MH ^<+> ).

4- (5-Cyclohexenyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -N, N-diethylthiazol-2-amine (I-12)

Compound (IIa-12) (17 mg, 35 μmol) in EtOH (1 mL) and 10% aqueous NaOH (0.5 mL) was added as described in General Procedure A for the deprotection of 7-azaindole. Deprotected by refluxing for hours. The crude product (I-12) was obtained as an off-white solid (11.3 mg, 32 μmol, 92%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.23 (t, J = 7.1 Hz, 6H), 1.60 to 1.67 (m, 2H), 1.73 to 1.81 (m, 2H) 2.15 to 2.22 (m, 2H), 2.41 to 2.48 (m, 2H), 3.50 (q, J = 7.1 Hz, 4H), 6.06 to 6.10 ( m, 1H), 6.49 (s, 1H), 7.65 (d, J = 2.5 Hz, 1H), 8.28 (d, J = 2.1 Hz, 1H), 8.33 (d, J = 2.1 Hz, 1H), 9.19 (s, 1H).

{4- [5- (4-Methyl-cyclohex-1-enyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -thiazol-2-yl} -morpholin-4-yl-methanone (I-13)

Crude bromide (XXIII-d) (110 mg, 0.28 mmol or less), 4-methyl-cyclohexene-1-in EtOH (1 ml), toluene (1 ml) and 1.0 M Na ₂ CO ₃ solution (0.5 ml). Irboronic acid (45 mg, 0.32 mmol), lithium chloride (40 mg, 0.95 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (25 mg, 36 μmol) were added using the general procedure A for Suzuki reaction for 2 hours. The reaction was carried out under reflux. The crude product (109 mg) by LCMS (column LUNA 10 μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. ) To give (I-13) (12 mg, 29 μmol, 10%) as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.5 Hz, 3H), 1.25 to 1.37 (m, 1H), 1.52 to 1.85 (m, 3H) 2.17 to 2.27 (m, 1H), 2.38 to 2.45 (m, 2H), 3.67 to 3.79 (m, 6H), 4.48 to 4.59 (m, 2H), 5.96 to 6.01 (m, 1H), 7.44 (s, 1H), 7.64 (s, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8 .31 (s, 1H), 9.68 (br s, 1H). MS (CI) m / z 409 (MH ^<+> ).

{4- [5- (4-Methyl-cyclohex-1-enyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -thiazol-2-yl}-(4-methyl-piperazine- 1-yl) -methanone (I-14)

Crude bromide (XXIII-e) (110 mg, 0.27 mmol or less), 4-methyl-cyclohexene-1-in EtOH (1 mL), toluene (1 mL) and 1.0 M Na ₂ CO ₃ solution (0.5 mL). Irboronic acid (45 mg, 0.32 mmol), lithium chloride (40 mg, 0.95 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (25 mg, 36 μmol) were added using the general procedure A for Suzuki reaction for 2 hours. The reaction was carried out under reflux. The crude product (89 mg by LCMS (column LUNA 10 μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. ) To give (I-14) (42 mg, 99 μmol, 37%) as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.07 (d, J = 6.4 Hz, 3H), 1.39 to 1.53 (m, 1H), 1.75 to 1.99 (m, 3H) 2.33 to 2.37 (m, 1H), 2.40 (s, 3H), 2.48 to 2.68 (m, 6H), 3.88 to 3.96 (m, 2H), 4 .80 to 4.88 (m, 2H), 6.11 to 6.16 (m, 1H), 7.57 (s, 1H), 7.78 (s, 1H), 8.39 (d, J = 1.9 Hz, 1H), 8.40 (d, J = 1.9 Hz, 1H), 10.38 (brs, 1H). MS (CI) m / z 422 (MH ^<+> ).

4- (5- (4,4-Dimethylcyclohexa-1,5-dienyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole-2-carboxylic acid (I-15)

Compound (IIa-35) (112 mg, 0.22 mmol) in EtOH (2 mL) and 10% aqueous NaOH (1 mL) was refluxed for 1 h as described in General Procedure A for 7-azaindole deprotection. By deprotection. The reaction mixture was concentrated to about 5 mL and neutralized by adding AcOH dropwise. The precipitate was filtered off to give crude product (I-15) (61 mg, 0.18 mmol, 83%) as a brown powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.06 (s, 6H), 2.30 (d, J = 4.7 Hz, 2H), 5.80 (dd, J = 0.6, 9. 8 Hz, 1H), 6.16 (t, J = 4.7 Hz, 1H), 6.36 (dd, J = 1.6, 9.7 Hz, 1H), 8.01 (s, 1H), 8. 10 (s, 1H), 8.37 (d, J = 2.1 Hz, 1H), 8.44 (d, J = 2.1 Hz, 1H), 11.94 (brs, 1H).

{4- [5- (4,4-Dimethyl-cyclohexa-1,5-dienyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -thiazol-2-yl} -morpholine-4- Il-methanone (I-16)

Compound (I-15) (30 mg, 88 μmol), diisopropylethylamine (20 mg, 0.15 mmol), morpholine (30 mg, 0.34 mmol) and BOP (75 mg, 0.17 mmol) in DMF (1 mL) were stirred for 3 days. And converted to (I-16) by following the general procedure for amide formation. Purify the crude reaction mixture by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent (I-16) (14.5 mg, 34 μmol, 39%) was obtained as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.13 (s, 6H), 2.36 (d, J = 4.6 Hz, 2H), 3.85 to 3.91 (m, 6H), 4.64 To 4.71 (m, 2H), 5.83 (d, J = 9.8 Hz, 1H), 6.06 (t, J = 4.6 Hz, 1H), 6.24 (d, J = 9. 8 Hz, 1 H), 7.60 (s, 1 H), 7.77 (d, J = 2.6 Hz, 1 H), 8.34 (d, J = 1.9 Hz, 1 H), 8.47 (d, J = 2.0 Hz, 1H), 8.97 (brs, 1H). MS (CI) m / z 421 (MH ^<+> ).

{4- [5- (4,4-Dimethyl-cyclohexa-1,5-dienyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -thiazol-2-yl}-(4-methyl -Piperazin-1-yl) -methanone (I-17)

Compound (I-15) (30 mg, 88 μmol), diisopropylethylamine (20 mg, 0.15 mmol), N-methylpiperazine (30 mg, 0.30 mmol) and BOP (75 mg, 0.17 mmol) in DMF (1 mL) Conversion to (I-16) by stirring for 3 days and following the general procedure for amide formation. Purify the crude reaction mixture by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent (I-17) (13.9 mg, 32 μmol, 36%) was obtained as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.03 (s, 6H), 2.28 (d, J = 4.7 Hz, 2H), 2.41 (s, 3H), 2.61 to 2.74 (M, 4H), 3.81 to 3.91 (m, 2H), 4.56 to 4.67 (m, 2H), 5.72 (dd, J = 0.8, 9.8 Hz, 1H) 5.95 (t, J = 4.5 Hz, 1H), 6.14 (dd, J = 1.6, 9.8 Hz, 1H), 7.51 (s, 1H), 7.71 (s, 1H), 8.27 (s, 2H). MS (CI) m / z 434 (MH ^<+> ).

4- (5- (4-Methylcyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole-2-carboxylic acid (I-18)

Compound (IIa-38) (540 mg) using the general procedure for hydrogenation of 7-azaindole over 3 days using 20% Pd (OH) ₂ / C (Degussa form, 100 mg) in MeOH (25 mL). , 0.99 mmol). The reaction mixture was then filtered through celite and concentrated to give the crude reduction product (IIb-18) (524 mg, crude yield 96%) as an oil. By refluxing the crude compound (IIb-18) (524 mg) in EtOH (10 mL) and 10% aqueous NaOH (5 mL) for 1 h as described in General Procedure A for 7-azaindole deprotection. Deprotected. The reaction mixture was concentrated to about 5 mL and neutralized by adding AcOH dropwise. The precipitate was filtered off to give a crude mixture of diastereoisomeric acids (I-18) (xx mg, xx%), which was used without further purification.

4- [5- (4-Methyl-cyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -thiazole-2-carboxylic acid dimethylamide (I-19)

Compound (I-18) (48 mg, 0.14 mmol), diisopropylethylamine (100 mg, 0.77 mmol), dimethylamine hydrochloride (40 mg, 0.49 mmol) and BOP (150 mg, 0.004) in DMF (1.5 mL). 29 mmol) was converted to (I-19) by stirring for 2 h and following the general procedure for amide formation. Purify the crude reaction mixture by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent (I-19) (34 mg, 92 μmol, 66%) was obtained as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.00 (d, J = 6.7 Hz, 1.2 H), 1.09 (d, J = 7.1 Hz, 1.8 H), 1.11-1. 23 (m, 1H), 1.49 to 2.08 (m, 8H), 2.62 to 2.71 (m, 0.4H), 2.72 to 2.81 (m, 0.6H), 3.25 (s, 3H), 3.80 (s, 1.2H), 3.81 (s, 1.8H), 7.56 (s, 1H), 7.82 (s, 1H), 8 .24 (d, J = 1.9 Hz, 0.4H), 8.27 (d, J = 1.9 Hz, 0.6H), 8.32 (d, J = 1.9 Hz, 0.4H), 8.37 (d, J = 1.9 Hz, 0.6H), 10.43 (br s, 1H). MS (CI) m / z 369 (MH ^<+> ).

{4- [5- (4-Methyl-cyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -thiazol-2-yl} -piperidin-1-yl-methanone (I-20)

Compound (I-18) (65 mg, 0.23 mmol), diisopropylethylamine (100 mg, 0.77 mmol), piperidine (50 mg, 0.59 mmol) and BOP (200 mg, 0.38 mmol) in DMF (1.5 mL). Conversion to (I-20) by stirring for 3 hours and following the general procedure for amide formation. Purify the crude reaction mixture by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent (I-20) (33 mg, 81 μmol, 35%) was obtained as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.00 (d, J = 6.6 Hz, 1.2 H), 1.10 (d, J = 7.2 Hz, 1.8 H), 1.12 to 1. 23 (m, 1H), 1.43 to 2.10 (m, 14H), 2.61 to 2.71 (m, 0.4H), 2.71 to 2.81 (m, 0.6H), 3.74 to 3.89 (m, 2H), 4.39 to 4.54 (m, 2H), 7.54 (s, 1H), 7.79 (s, 1H), 8.26 (d, J = 1.8 Hz, 0.4 H), 8.28 (d, J = 1.8 Hz, 0.6 H), 8.29 (d, J = 2.0 Hz, 0.4 H), 8.32 (d , J = 2.0 Hz, 0.6H), 9.85 (br s, 1H). MS (CI) m / z 409 (MH ^<+> ).

{4- [5- (4-Methyl-cyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -thiazol-2-yl} -morpholin-4-yl-methanone (I-21)

Compound (I-18) (65 mg, 0.23 mmol), diisopropylethylamine (100 mg, 0.77 mmol), morpholine (50 mg, 0.57 mmol) and BOP (200 mg, 0.38 mmol) in DMF (1.5 mL). Conversion to (I-20) by stirring for 3 hours and following the general procedure for amide formation. Purify the crude reaction mixture by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent (I-21) (38 mg, 93 μmol, 40%) was obtained as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.00 (d, J = 6.6 Hz, 1.2H), 1.10 (d, J = 7.2 Hz, 1.8H), 1.13-1. 24 (m, 1H), 1.48 to 2.11 (m, 8H), 2.62 to 2.72 (m, 0.4H), 2.73 to 2.82 (m, 0.6H), 3.80 to 3.97 (m, 6H), 4.63 to 4.76 (m, 2H), 7.59 (s, 1H), 7.81 (s, 1H), 8.23 (d, J = 1.9 Hz, 0.4H), 8.26 (d, J = 1.9 Hz, 0.6H), 8.29 (d, J = 2.0 Hz, 0.4H), 8.33 (d , J = 2.0 Hz, 0.6H), 10.26 (br s, 1H). MS (CI) m / z 411 (MH ^<+> ).

{4- [5- (4-Methyl-cyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -thiazol-2-yl}-(4-methyl-piperazin-1-yl)- Methanone (I-22)

Compound (I-18) (65 mg, 0.23 mmol), diisopropylethylamine (100 mg, 0.77 mmol), N-methylpiperazine (50 mg, 0.50 mmol) and BOP (200 mg, 0.25 mmol) in DMF (1.5 mL). 38 mmol) was converted to (I-20) by stirring for 3 hours and following the general procedure for amide formation. Purify the crude reaction mixture by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent (I-22) was obtained as a white powder (36 mg, 85 μmol, 37%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.4 Hz, 1.2 H), 1.00 (d, J = 7.2 Hz, 1.8 H), 1.03-1. 14 (m, 1H), 1.42 to 2.00 (m, 8H), 2.32 (s, 1.8H), 2.32 (s, 1.8H), 2.46 to 2.62 ( m, 5.4H), 2.63 to 2.72 (m, 0.6H), 3.76 to 3.91 (m, 2H), 4.49 to 4.65 (m, 2H), 7. 47 (s, 1H), 7.70 (s, 1H), 8.13-8.25 (m, 2H), 10.19 (brs, 1H). MS (CI) m / z 424 (MH ^<+> ).

5- (1,4-Dioxa-spiro [4.5] dec-8-yl) -3- [2- (1-methyl-piperidin-4-yl) -thiazol-4-yl] -1H-pyrrolo [ 2,3-b] pyridine (I-23)

Using the general procedure for hydrogenation of 7-azaindole using 20% Pd (OH) ₂ / C (Degussa form, 40 mg) in MeOH (5 mL) —CH ₂ Cl ₂ (5 mL) over 20 h. Compound (IIa-36) (148 mg, 0.26 mmol) was hydrogenated. The reaction mixture was then filtered through celite and concentrated to give the crude reduction product (IIb-23) (131 mg) as an oil. By refluxing the crude compound (IIb-23) (131 mg) in EtOH (2 mL) and 10% aqueous NaOH (1 mL) for 1 h as described in General Procedure A for 7-azaindole deprotection. Deprotected. The crude product was then purified by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. (I-23) (92 mg) was purified to give (I-23) (13.5 mg, 30 μmol, 14%) as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.76 to 1.83 (m, 2H), 1.89 to 2.03 (m, 6H), 2.26 to 2.35 (m, 2H), 2 .38 to 2.50 (m, 5H), 2.72 to 2.82 (m, 1H), 3.13 to 3.25 (m, 5H), 4.04 (s, 4H), 7.27 (S, 1H), 7.80 (s, 1H), 8.19 (d, J = 1.9 Hz, 1H), 8.26 (d, J = 1.9 Hz, 1H), 10.18 (s , 1H). MS (CI) m / z 453 (MH ^<+> ).

2- (5-Cyclohexenyl-1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole (I-24)

Compound (IIa-24) (25 mg, 59 μmol) in EtOH (1 mL) and 10% aqueous NaOH (0.5 mL) was refluxed for 90 minutes as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product (I-24) (15 mg, 39 μmol, 66%) was obtained as an off-white powder that did not require further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.61 to 1.68 (m, 2H), 1.75 to 1.82 (m, 2H), 2.17 to 2.23 (m, 2H), 2 .44 to 2.50 (m, 2H), 6.09 to 6.13 (m, 1H), 7.17 (d, J = 3.3 Hz, 1H), 7.78 (d, J = 3. 3 Hz, 1 H), 7.88 (s, 1 H), 8.40 (d, J = 2.1 Hz, 1 H), 8.49 (d, J = 2.1 Hz, 1 H), 10.65 (br s , 1H).

{4- [5- (1,4-Dioxa-spiro [4.5] dec-8-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -thiazol-2-yl}- Piperidin-1-yl-methanone (I-25)

Compound (IIb-25) (103 mg, 0.17 mmol) in EtOH (2 mL) and 10% aqueous NaOH (1 mL) was refluxed for 1 h as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product was then purified by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. (I-25) (61 mg) was purified to give (I-25) (3 mg, 6.6 μmol, 4%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.72 to 2.04 (m, 14H), 2.73 to 2.83 (m, 1H), 3.78 to 3.87 (m, 2H), 4 .03 (s, 4H), 4.46 to 4.55 (m, 2H), 7.55 (s, 1H), 7.80 (d, J = 2.5 Hz, 1H), 8.31 (d , J = 1.9 Hz, 1H), 8.33 (d, J = 1.9 Hz, 1H), 9.80 (s, 1H). MS (CI) m / z 453 (MH ^<+> ).

2- (5-Cyclohexyl-1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole (I-26)

Compound (IIb-26) (55 mg, 0.13 mmol) in EtOH (2 mL) and 10% aqueous NaOH (1 mL) was refluxed for 90 min as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product (I-26) was obtained as an off-white powder (34.5 mg, 0.12 mmol, 94%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.16-1.60 (m, 5H), 1.68-1.95 (m, 5H), 2.66 (tt, J = 3.4, 12. 0 Hz, 1H), 7.17 (d, J = 3.3 Hz, 1H), 7.78 (d, J = 3.3 Hz, 1H), 7.87 (s, 3H), 8.23 (d, J = 2.0 Hz, 1H), 8.37 (d, J = 2.0 Hz, 1H), 10.35 (br s, 1H).

{4- [5- (4-Ethyl-cyclohex-1-enyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -thiazol-2-yl} -morpholin-4-yl-methanone (I-27)

Crude bromide (XXIII-d) (150 mg, 0.38 mmol or less), 4-ethyl-cyclohexene-1-in EtOH (1 mL), toluene (1 mL) and 1.0 M Na ₂ CO ₃ solution (1.0 mL). Irboronic acid (117 mg, 0.76 mmol), lithium chloride (48 mg, 1.14 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (26.7 mg, 38 μmol) were prepared using general procedure A for the Suzuki reaction. The reaction was carried out under reflux for 6 hours. The crude product (109 mg) was purified by PTLC using AcOEt as the eluent to give (I-27) (32 mg, 20%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.99 (t, J = 7.4 Hz, 3H), 1.35 to 1.49 (m, 3H), 1.52 to 1.64 (m, 1H) 1.84 to 1.95 (m, 1H), 1.97 to 2.05 (m, 1H), 2.35 to 2.45 (m, 1H), 2.53 to 2.61 (m, 1H) 2H), 3.83 to 3.95 (m, 6H), 4.65 to 4.73 (m, 2H), 6.12 to 6.18 (m, 1H), 7.57 (s, 1H) 7.82 (s, 1H), 8.34 (d, J = 1.8 Hz, 1H), 8.49 (d, J = 1.8 Hz, 1H), 11.26 (brs, 1H).

4- (5-((1s, 4s) -4-morpholinocyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole-2-carboxylic acid (I-28)

The crude compound (IIb-46) (138 mg, 0.24 mmol) in EtOH (6 mL) and 10% aqueous NaOH (3 mL) was added at 80 ° C. as described in General Procedure A for 7-azaindole deprotection. Was deprotected by heating for 2 hours 15 minutes. The reaction mixture was concentrated to about 3 mL and neutralized by adding AcOH dropwise. A yellow semi-solid was formed. The supernatant was removed and the yellow solid was dried in vacuo overnight to give the crude product (I-28) (99 mg, 99%), which was used without further purification.

4- (5-((1r, 4r) -4-morpholinocyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole-2-carboxylic acid (I-29)

The crude compound (IIb-47) (148 mg, 0.26 mmol) in EtOH (6 mL) and 10% aqueous NaOH (3 mL) was added at 80 ° C. as described in General Procedure A for 7-azaindole deprotection. Was deprotected by heating for 3 hours. The reaction mixture was concentrated to about 3 mL and neutralized by adding AcOH dropwise. The solvent was evaporated to give a yellow solid. Water (1 mL) was added to the solid and the mixture was stirred for 5 minutes. The solid was filtered off to give (I-29) (55 mg, 51%), which was used without further purification.

(4- (5-((1r, 4r) -4-morpholinocyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazol-2-yl) (piperidin-1-yl) methanone ( I-30)

Compound (I-28) (33 mg, 0.08 mmol), diisopropylethylamine (0.14 mL, 0.80 mmol), piperidine (14 mg, 0.16 mmol) and BOP (70 mg, 0.16 mmol) in DMF (1 mL). , Converted to (I-30) by stirring overnight and following the general procedure for amide formation. Purify the crude reaction mixture by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent Compound (I-30) was obtained as a white solid (7 mg, 18%; retention time 16.3 to 16.7 minutes); MS (CI) m / z 480.2 (MH ^<+> ).

Morpholino (4- (5-((1s, 4s) -4-morpholinocyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazol-2-yl) methanone (I-31)

Compound (I-28) (33 mg, 0.08 mmol), diisopropylethylamine (0.14 mL, 0.80 mmol), morpholine (14 mg, 0.16 mmol) and BOP (70 mg, 0.16 mmol) in DMF (1 mL). , Converted to (I-31) by stirring overnight and following the general procedure for amide formation. Purify the crude reaction mixture by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent Compound (I-31) (2 mg, 5%; retention time 15.5 to 16.5 minutes) was obtained as a white solid; MS (CI) m / z 482.2 (MH ^<+> ).

(4-Methylpiperazin-1-yl) (4- (5-((1s, 4s) -4-morpholinocyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazol-2-yl ) Methanone (I-32)

Compound (I-28) (33 mg, 0.08 mmol), diisopropylethylamine (0.14 mL, 0.80 mmol), N-methylpiperazine (16 mg, 0.16 mmol) and BOP (70 mg, 0. 0) in DMF (1 mL). 16 mmol) was converted to (I-31) by stirring overnight and following the general procedure for amide formation. Purify the crude reaction mixture by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent Compound (I-32) (7 mg, 18%; retention time 12.6 to 13.1 minutes) was obtained as a colorless oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.56-1. 66 (m, 2H), 1.67 to 1.76 (m, 2H), 197 to 2.01 (m, 2H), 2.02 to 2.06 (m, 4H), 2.25 to 2. 34 (m, 2H), 2.36 (s, 3H), 2.50 to 2.55 (m, 4H), 2.59 (t, J = 5.0 Hz, 4H), 3.76 (t, J = 4.8 Hz, 4H), 3.85 to 3.90 (m, 2H), 4.55 to 4.61 (m, 2H), 7.56 (s) 1H), 7.76 (s, 1H), 7.98 (brs, NH, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 1.8 Hz) , 1H), MS (CI) m / z 495.2 (MH ^<+> ).

(4- (5-((1r, 4r) -4-morpholinocyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazol-2-yl) (piperidin-1-yl) methanone ( I-33)

Compound (I-29) (27 mg, 0.066 mmol), diisopropylethylamine (0.12 mL, 0.66 mmol), piperidine (34 mg, 0.40 mmol) and BOP (59 mg, 0.13 mmol) in DMF (1 mL). , Converted to (I-33) by stirring overnight and following the general procedure for amide formation. Purify the crude reaction mixture by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent Compound (I-33) (5.8 mg, 18%; retention time 17.2 to 17.8 minutes) was obtained as a yellow solid; ¹ H NMR (400 MHz, CH ₃ CN) δ 1.69 To 1.81 (m, 10H), 2.13 to 2.19 (m, 2H), 2.25 to 2.30 (m, 2H), 2.78 to 2.88 (m, 1H), 3 .16-3.36 (m, 3H), 3.45 (d, J = 12.3 Hz, 2H), 3.71-3.79 (m, 2H), 3.82 (d, J = 12 Hz, 2H), 4.11 (dd, J = 3.0 and 13.0 Hz, 2H), 4.36 to 4.42 (m, 2H), 7 82 (s, 1H), 7.95 (s, 1H), 8.26 (s, 1H), 8.45 (d, J = 1.5 Hz, 1H), 10.1 (brs, NH, 1H) ); MS (CI) m / z 480.2 (MH ^<+> ).

Morpholino (4- (5-((1r, 4r) -4-morpholinocyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazol-2-yl) methanone (I-34)

Compound (I-29) (27 mg, 0.066 mmol), diisopropylethylamine (0.12 mL, 0.66 mmol), morpholine (35 mg, 0.40 mmol) and BOP (59 mg, 0.13 mmol) in DMF (1 mL). , Converted to (I-34) by stirring overnight and following the general procedure for amide formation. Purify the crude reaction mixture by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) as eluent (gradient; flow rate 80 mL / min). Compound (I-34) (9 mg, 28%; retention time 14.2-15.0 minutes) was obtained as a yellow solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.41-1. 52 (m, 2H), 1.53 to 1.65 (m, 2H), 2.02 to 2.15 (m, 4H), 2.41 to 2.50 (m, 1H), 2.62 to 2.68 (m, 1H), 2.70 (t, J = 4.4 Hz, 4H), 2.95-2.97 (m, 4H), 3.77 (t, J = 4.4 Hz, 4H) ) 3.79-3.82 (m, 4H), 7.54 (s, 1H), 7.73 (s, 1H), 8.12 (s, 1H) , 8.14 (d, J = 1.9Hz , 1H), MS (CI) m / z 482.2 (MH +).

5- (5-Cyclohexyl-1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole (I-48)

Iodide (IXb-6) and 5- (tributylstannyl) thiazole were reacted using the general procedure B for Stille reaction (25% yield), followed by the general deprotection of 7-azaindole. Deprotection according to general procedure A (yield 70%). The crude product was purified by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. (I-48) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.28 to 1.66 (m, 5H), 1.78 to 2.04 (m, 5H), 2.73 (tt, J = 3.5, 11. 8 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 2.1 Hz, 1H), 8.25 (d, J = 1.9 Hz, 1H), 8.30 (d, J = 1.9 Hz, 1H), 8.95 (d, J = 2.0 Hz, 1H), 10.00 (brs, 1H).

4- (5-cyclohexyl-1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole (I-49)

Iodide (IXb-6) and 4- (tributylstannyl) thiazole were reacted using the general procedure B for Stille reaction (25% yield) followed by the general deprotection of 7-azaindole. Deprotection according to general procedure A (58% yield). The crude product was purified by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. (I-49) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.28 to 1.63 (m, 5H), 1.79 to 2.04 (m, 5H), 2.72 (tt, J = 3.4, 11. 8 Hz, 1H), 7.60 (d, J = 2.2 Hz, 1H), 8.03 (d, J = 1.9 Hz, 1H), 8.11 (s, 1H), 8.32 (d, J = 1.9 Hz, 1H), 8.78 (s, 1H), 10.19 (brs, 1H).

4- (5-Cyclohexyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -2-methoxythiazole (I-50)

Iodide (IXb-6) and 2-methoxy-4- (tributylstannyl) thiazole were reacted using General Procedure B for Stille reaction (62% yield) followed by 7-azaindole. Deprotection was performed according to general procedure A for deprotection (87% yield). The crude product was purified by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. (I-50) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.16 to 1.55 (m, 5H), 1.67 to 1.94 (m, 5H), 2.62 (tt, J = 3.4, 11. 8 Hz, 1 H), 4.11 (s, 3 H), 6.67 (s, 1 H), 7.70 (d, J = 2.2 Hz, 1 H), 8.08 (d, J = 1.9 Hz, 1H), 8.17 (d, J = 1.9 Hz, 1H), 8.78 (s, 1H), 9.96 (brs, 1H).

2- (5-cyclohexyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -4-methylthiazole (I-51)

Iodide (IXb-6) and 4-methyl-2- (tributylstannyl) thiazole were reacted using General Procedure B for Stille reaction (63% yield) followed by 7-azaindole. Deprotection was performed according to general procedure A of deprotection (49% yield). The crude product was purified by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. (I-51) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.16 to 1.51 (m, 5H), 1.63 to 1.89 (m, 5H), 2.41 (s, 3H), 2.59 (tt , J = 3.3, 11.9 Hz, 1H), 6.66 (d, J = 1.0 Hz, 1H), 7.81 (d, J = 1.1 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 10.52 (brs, 1H).

2- (5-cyclohexyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-methylthiazole (I-52)

Iodide (IXb-6) and 5-methyl-2- (tributylstannyl) thiazole were reacted using General Procedure B for Stille reaction (32% yield) followed by 7-azaindole. Deprotection was performed according to general procedure A for deprotection (61% yield). The crude product was purified by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. (I-52) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.24 to 1.65 (m, 5H), 1.77 to 2.02 (m, 5H), 2.54 (s, 3H), 2.72 (tt , J = 3.2, 11.7 Hz, 1H), 7.49 (d, J = 1.2 Hz, 1H), 7.83 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 10.94 (brs, 1H).

4- (5-cyclohexyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -2-ethoxythiazole (I-53)

Iodide (IXb-6) and 2-ethoxy-4- (tributylstannyl) thiazole were reacted using General Procedure B for Stille reaction (63% yield) followed by 7-azaindole. Deprotection was performed according to general procedure A for deprotection (93% yield). The crude product was purified by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. (I-53) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.16 to 1.53 (m, 8H), 1.69 to 1.94 (m, 5H), 2.61 (tt, J = 3.3, 11. 8 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 6.66 (s, 1H), 7.68 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 1.9 Hz, 1H), 8.17 (d, J = 1.9 Hz, 1H), 9.66 (brs, 1H).

4-((1r, 4r) -4- (3- (2-methylthiazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (I-55)

Compound (IIb-55) (491 mg, 0.94 mmol) in EtOH (4 mL) and 10% aqueous NaOH (2 mL) was refluxed for 90 minutes as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product was obtained as a yellow powder (350 mg), which was purified by trituration with Et ₂ O (5 mL) to give (I-55) as a white powder (251 mg, 0.66 mmol). 70%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.41-1.73 (m, 4H), 2.06-2.18 (m, 4H), 2.39 (tt, J = 3.3, 11. 5 Hz, 1H), 2.60-2.76 (m, 5H), 2.83 (s, 3H), 3.79 (t, J = 4.6 Hz, 4H), 7.22 (s, 1H) 7.82 (d, J = 2.6 Hz, 1H), 8.16 (d, J = 1.9 Hz, 1H), 8.26 (d, J = 2.1 Hz, 1H), 9.07 ( br s, 1H).

4-((1s, 4s) -4- (3- (2-methylthiazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (I-56)

Compound (IIb-56) (411 mg, 0.79 mmol) in EtOH (4 mL) and 10% aqueous NaOH (2 mL) was refluxed for 90 min as described in General Procedure A for 7-azaindole deprotection. By deprotection. The product (I-56) was obtained as an off-white powder (218 mg, 0.57 mmol, 72%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.54 to 1.76 (m, 4H), 2.00 to 2.13 (m, 4H), 2.29 to 2.34 (m, 1H), 2 .47 to 2.59 (m, 5H), 2.81 to 2.92 (m, 4H), 3.80 (t, J = 4.6 Hz, 2H), 7.22 (s, 1H), 7 .82 (d, J = 2.6 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 9.01 (br s , 1H).

4- (5-Cyclohexenyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -2-methylthiazole (I-57)

Compound (IIa-57) (44 mg, 0.10 mmol) in EtOH (1 mL) and 10% aqueous NaOH (0.5 mL) was prepared as described in General Procedure A for 7-azaindole deprotection. Deprotected by refluxing for minutes. The crude product (23 mg) was purified by trituration with Et ₂ O (2 mL) to give (I-57) (18 mg, 0.05 mmol, 17%) as an off-white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.60 to 1.68 (m, 2H), 1.74 to 1.82 (m, 2H), 2.16 to 2.22 (m, 2H), 2 .42 to 2.48 (m, 2H), 2.73 (s, 3H), 6.04 to 6.09 (m, 1H), 7.15 (s, 1H), 7.74 (d, J = 2.5 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 9.19 (brs, 1H).

4- (5-cyclohexyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -2-methylthiazole (I-58)

Compound (IIb-58) (133 mg, 0.30 mmol) in EtOH (2 mL) and 10% aqueous NaOH (1.0 mL) was prepared as described in General Procedure A for 7-azaindole deprotection. Deprotected by refluxing for minutes. The crude product by preparative LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent To give (I-58) (16 mg, 0.05 mmol, 17%) as an off-white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.30 to 1.63 (m, 5H), 1.78 to 2.03 (m, 5H), 2.66 to 2.76 (m, 1H), 2 .83 (s, 3H), 7.23 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 1.9 Hz, 1H), 8.26 (D, J = 2.0 Hz, 1H), 9.28 (brs, 1H).

4-((1r, 4r) -4- (3- (thiazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (I-59)

Iodide (IXb-29) and 4-tributylstannylthiazole were reacted using General Procedure B for Stille reaction (57% yield) followed by general procedure for 7-azaindole deprotection Deprotected according to B (69% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.33 to 1.46 (m, 2H), 1.57 to 1.71 (m, 2H), 1.89 to 2.02 (m, 4H) 2.30 to 2.41 (m, 1H), 2.50 to 2.59 (m, 1H), 3.59 (t, J = 4.4 Hz, 4H), 7.95 (d, J = 1.9 Hz, 1H), 7.97 (d, J = 2.6 Hz, 1H), 8.18 (d, J = 1.9 Hz, 1H), 8.33 (d, J = 1.8 Hz, 1H) ), 9.20 (d, J = 1.8 Hz, 1H), 11.79 (d, J = 1.8 Hz, 1H). An aliphatic peak is hidden under the solvent peak of about 2.5 ppm.

4-((1r, 4r) -4- (3- (thiazol-5-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (I-60)

Iodide (IXb-29) and 5-tributylstannylthiazole were reacted using General Procedure B for Stille reaction (44% yield) followed by general procedure for 7-azaindole deprotection Deprotected according to B (86% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.40 to 1.54 (m, 2H), 1.56 to 1.71 (m, 2H), 2.05 to 2.18 (m, 4H), 2 .34 to 2.43 (m, 1H), 2.61 to 2.75 (m, 5H), 3.78 (t, J = 4.4 Hz, 4H), 7.56 (d, J = 1. 7 Hz, 1 H), 7.99 to 8.01 (m, 1 H), 8.06 to 8.10 (m, 1 H), 8.22 to 8.32 (m, 1 H), 8.76 to 8. 79 (m, 1H).

4-((1r, 4r) -4- (3- (4-methylthiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (I-61)

Iodide (IXb-29) and 4-methyl-2-tributylstannylthiazole were reacted using General Procedure B for Stille reaction (39% yield) followed by deprotection of 7-azaindole Was deprotected according to general procedure B. (75% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.40 to 1.54 (m, 2H), 1.56 to 1.71 (m, 2H), 2.05 to 2.18 (m, 4H), 2 .34 to 2.43 (m, 1H), 2.61 to 2.75 (m, 5H), 3.78 (t, J = 4.4 Hz, 4H), 7.56 (d, J = 1. 7 Hz, 1 H), 7.99 to 8.01 (m, 1 H), 8.06 to 8.10 (m, 1 H), 8.22 to 8.32 (m, 1 H), 8.76 to 8. 79 (m, 1H).

4-((1r, 4r) -4- (3- (5-methylthiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (I-62)

Iodide (IXb-29) and 5-methyl-2-tributylstannylthiazole were reacted using General Procedure B for Stille reaction (9% yield) followed by deprotection of 7-azaindole Was deprotected according to general procedure B. (75% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.40 to 1.52 (m, 2H), 1.61 to 1.74 (m, 2H), 2.05 to 2.17 (m, 4H), 2 .36 to 2.43 (m, 1H), 2.54 (d, J = 1.1 Hz, 3H), 2.61 to 2.75 (m, 5H), 3.78 (t, J = 4. 6 Hz, 4H), 7.49 (q, J = 1.1 Hz, 1H), 7.80 (d, J = 2.8 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 8.79 (brs, 1H).

4-((1r, 4r) -4- (3- (2-ethoxythiazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (I-63)

Iodide (IXb-29) and 2-ethoxy-4-tributylstannylthiazole were reacted using General Procedure B for Stille reaction (80% yield) followed by deprotection of 7-azaindole Was deprotected according to general procedure B. (yield 85%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.42 to 1.74 (m, 7H), 2.07 to 2.20 (m, 4H), 2.33 to 2.44 (m, 1H), 2 .59 to 2.74 (m, 5H), 3.76 to 3.84 (m, 4H), 4.58 (q, J = 7.1 Hz, 2H), 6.75 (s, 1H), 8 .15 (d, J = 1.8 Hz, 1H), 8.25 (d, J = 1.8 Hz, 1H), 9.36 (brs, 1H).

4-((1r, 4r) -4- (3- (4,5-dimethylthiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (I-64 )

Iodide (IXb-29) and 4,5-dimethyl-2-tributylstannylthiazole were reacted using General Procedure B for Stille reaction (43% yield) followed by 7-azaindole. Deprotection was according to general procedure B of deprotection (yield 50%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.41 to 1.55 (m, 2H), 1.60 to 1.74 (m, 2H), 2.06 to 2.19 (m, 4H), 2 .35 to 2.47 (m, 7H), 2.61 to 2.77 (m, 5H), 3.75 to 3.85 (m, 4H), 7.85 (s, 1H), 8.28 (S, 1H), 8.34 (s, 1H), 9.49 (brs, 1H).

4-((1r, 4r) -4- (3- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (I -69)

Compound (IIb-69) (78 mg, 0.14 mmol) in EtOH (3 mL) and 10% aqueous NaOH (1.5 mL) was added as described in General Procedure A for 7-azaindole deprotection. Deprotected by refluxing for minutes. The crude product was purified by trituration with Et ₂ O (2 mL) to give (I-69) (37 mg, 0.08 mmol, 63%) as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.43 to 1.75 (m, 4H), 2.08 to 2.21 (m, 4H), 2.37 to 2.48 (m, 1H), 2 .64 to 2.80 (m, 5H), 3.79 (t, J = 4.5 Hz, 4H), 7.67 (s, 1H), 8.00 (d, J = 2.6 Hz, 1H) 8.33 (d, J = 1.9 Hz, 1H), 8.40 (d, J = 1.9 Hz, 1H), 9.87 (brs, 1H).

4-((1s, 4s) -4- (3- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (I -70)

Compound (IIb-70) (58 mg, 0.14 mmol) in EtOH (3 mL) and 10% aqueous NaOH (1.5 mL) was prepared as described in General Procedure A for 7-azaindole deprotection. Deprotected by refluxing for minutes. The crude product was purified by trituration with Et ₂ O (2 mL) to give (I-70) (30 mg, 0.07 mmol, 68%) as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.55 to 1.77 (m, 4H), 2.00 to 2.15 (m, 4H), 2.29 to 2.35 (m, 1H), 2 .47 to 2.61 (m, 4H), 2.85 to 2.95 (m, 1H), 3.81 (t, J = 4.5 Hz, 4H), 7.66 (s, 1H), 7 .96 to 8.00 (m, 1H), 8.36 (d, J = 1.9 Hz, 1H), 8.52 (d, J = 1.9 Hz, 1H), 10.20 (br s, 1H) ).

2-Methyl-4- (5-((1r, 4r) -4- (pyrrolidin-1-yl) cyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole (I-74)

Compound (IIb-74) (177 mg, 0.35 mmol) in EtOH (4 mL) and 10% aqueous NaOH (2 mL) was refluxed for 90 min as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product (109 mg) was purified by trituration with Et ₂ O (5 mL) to give (I-74) (81 mg, 0.22 mmol, 63%) as a pale yellow powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.46-1.59 (m, 2H), 1.61-1.74 (m, 2H), 1.82-1.90 (m, 4H), 2 .02 to 2.10 (m, 2H), 2.14 to 2.27 (m, 3H), 2.65 to 2.78 (m, 5H), 2.83 (s, 3H), 7.23 (S, 1H), 7.84 (d, J = 2.5 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H) 9.46 (br s, 1H).

4-((1r, 4r) -4- (3- (2-methylthiazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepane ( I-75)

Compound (IIb-75) (343 mg, 0.64 mmol) in EtOH (4 mL) and 10% aqueous NaOH (2 mL) was refluxed for 90 min as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product (187 mg) was purified by trituration with Et ₂ O (5 mL) to give (I-75) (149 mg, 0.37 mmol, 59%) as a pale yellow powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.46 to 1.67 (m, 4H), 1.91 (quintet, J = 6.8 Hz, 2H), 1.99 to 2.14 (m, 4H), 2.63 to 2.76 (m, 1H), 2.83 (s, 3H), 2.84 to 2.91 (m, 4H), 3.75 to 3.80 (m, 2H) 3.85 (t, J = 5.9 Hz, 2H), 7.22 (s, 1H), 7.82 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 1. 9 Hz, 1 H), 8.26 (d, J = 1.9 Hz, 1 H), 9.14 (br s, 1 H).

4-((1s, 4s) -4- (3- (2-methylthiazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepane ( I-76)

Compound (IIb-76) (223 mg, 0.42 mmol) in EtOH (4 mL) and 10% aqueous NaOH (2 mL) was refluxed for 90 min as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product (125 mg) was purified by trituration with Et ₂ O (5 mL) to give (I-76) (93 mg, 0.23 mmol, 56%) as a pale yellow powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.59 to 1.71 (m, 2H), 1.71 to 1.81 (m, 2H), 1.89 (quintet, J = 5.8 Hz, 2H), 1.93 to 2.04 (m, 2H), 2.06 to 2.18 (m, 2H), 2.83 (s, 3H), 2.84 to 2.99 (m, 6H) 3.79 (t, J = 5.0 Hz, 2H), 3.84 (t, J = 5.8 Hz, 2H), 7.22 (s, 1H), 7.82 (d, J = 2. 6 Hz, 1H), 8.25 (d, J = 1.9 Hz, 1H), 8.33 (d, J = 1.9 Hz, 1H), 9.03 (brs, 1H).

4-((1r, 4r) -4- (3- (4- (1-methylpiperidin-4-yl) thiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) (Cyclohexyl) morpholine (I-78)

Compound (IIb-78) (276 mg, ˜80% purity, 0.36 mmol) in EtOH (3 mL) and 10% aqueous NaOH (1.5 mL) was described in General Procedure A for 7-azaindole deprotection. As deprotected, it was deprotected by refluxing for 90 minutes. The crude product (97 mg ) To give (I-78) (46 mg, 0.10 mmol, 27%) as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.49 to 1.73 (m, 4H), 2.10 to 2.24 (m, 6H), 2.30 to 2.39 (m, 2H), 2 .52 to 2.62 (m, 1H), 2.65 to 2.81 (m, 10H), 3.00 to 3.09 (m, 1H), 3.42 to 3.52 (m, 2H) 3.83 (t, J = 4.6 Hz, 4H), 6.88 (s, 1H), 7.89 (s, 1H), 8.21 (d, J = 1.9 Hz, 1H), 8 .39 (d, J = 1.9 Hz, 1H), 10.78 (brs, 1H).

4-((1s, 4s) -4- (3- (4- (1-methylpiperidin-4-yl) thiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) (Cyclohexyl) morpholine (I-79)

Compound (IIb-79) (149 mg, ˜80% purity, 0.20 mmol) in EtOH (3 mL) and 10% aqueous NaOH (1.5 mL) was described in General Procedure A for 7-azaindole deprotection. As deprotected, it was deprotected by refluxing for 90 minutes. The crude product (96 mg) was purified by trituration with Et ₂ O (2 mL) to give (I-79) (45 mg, 0.07 mmol, 49%) as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.56 to 1.76 (m, 4H), 1.86 to 2.00 (m, 2H), 2.02 to 2.26 (m, 8H), 2 .29 to 2.35 (m, 1H), 2.38 (s, 3H), 2.49 to 2.59 (m, 4H), 2.81 to 2.95 (m, 2H), 3.00 To 3.09 (m, 2H), 3.80 (t, J = 4.6 Hz, 4H), 6.83 (s, 1H), 7.89 (s, 1H), 8.34 (d, J = 1.9 Hz, 1H), 8.47 (d, J = 1.9 Hz, 1H), 9.54 (brs, 1H).

4-((1r, 4r) -4- (3- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1, 4-Oxazepan (I-80)

Compound (IIb-80) (97 mg, 0.16 mmol) in EtOH (2 mL) and 10% aqueous NaOH (1 mL) was refluxed for 90 min as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product (69 mg) was purified by trituration with _Et 2 O (2mL), to give (I-80) (48mg, 0.11mmol, 64%) as a pale yellow powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.56 to 1.75 (m, 4H), 1.87 to 1.99 (m, 2H), 2.02 to 2.15 (m, 4H), 2 .67 to 2.78 (m, 2H), 2.83 to 2.97 (m, 4H), 3.76 to 3.83 (m, 2H), 3.85 (t, J = 5.9 Hz, 2H), 7.67 (q, J = 0.9 Hz, 1H), 7.97 (s, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 9.19 (brs, 1H).

4-((1s, 4s) -4- (3- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1, 4-Oxazepane (I-81)

Compound (IIb-81) (74 mg, 0.13 mmol) in EtOH (2 mL) and 10% aqueous NaOH (1 mL) was refluxed for 90 min as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product (55 mg) was purified by trituration with Et ₂ O (2 mL) to give (I-81) (35 mg, 0.08 mmol, 62%) as a pale yellow powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.61-1.73 (m, 2H), 1.73-1.83 (m, 2H), 1.90 (quintet, J = 5.8 Hz, 2H), 1.95 to 2.06 (m, 2H), 2.08 to 2.20 (m, 2H), 2.81 to 3.02 (m, 6H), 3.80 (t, J = 4.9 Hz, 2H), 3.84 (t, J = 5.8 Hz, 2H), 7.66 (s, 1H), 8.02 (s, 1H), 8.39 (d, J = 2. 0 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 10.27 (brs, 1H).

2- (5-((1r, 4r) -4- (4-methylpiperazin-1-yl) cyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -4- (trifluoromethyl ) Thiazole (I-82)

Compound (IIb-82) (93 mg, 0.16 mmol) in EtOH (2 mL) and 10% aqueous NaOH (1 mL) was refluxed for 90 min as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product (43 mg) was purified by trituration with Et ₂ O (2 mL) to give (I-82) (34 mg, 0.08 mmol, 48%) as a pale yellow powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.45 to 1.58 (m, 2H), 1.60 to 1.75 (m, 2H), 2.05 to 2.18 (m, 4H), 2 .34 (s, 3H), 2.40 to 2.78 (m, 10H), 7.66 (q, J = 0.8 Hz, 1H), 8.02 (s, 1H), 8.33 (d , J = 2.0 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H), 10.31 (brs, 1H).

2- (5-((1s, 4s) -4- (4-methylpiperazin-1-yl) cyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -4- (trifluoromethyl ) Thiazole (I-83)

Compound (IIb-83) (40 mg, 0.068 mmol) in EtOH (2 mL) and 10% aqueous NaOH (1 mL) was refluxed for 90 min as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product (30 mg) was purified by trituration with hexane (2 mL) to give (I-83) (28 mg, 0.06 mmol, 92%) as a pale yellow powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.52 to 1.82 (m, 7H), 2.03 to 2.14 (m, 4H), 2.34 (s, 3H), (m, 4H) 2.40-2.77 (m, 5H), 2.87-2.96 (m, 1H), 7.66 (q, J = 0.9 Hz, 1H), 7.99 (s, 1H) 8.37 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 9.89 (brs, 1H).

2- (5-((1r, 4r) -4- (pyrrolidin-1-yl) cyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -4- (trifluoromethyl) thiazole ( I-84)

Compound (IIb-84) (23 mg, 0.04 mmol) in EtOH (2 mL) and 10% aqueous NaOH (1 mL) was refluxed for 90 min as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product (20 mg ) To give (I-84) (12 mg, 0.03 mmol, 71%) as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.59 to 1.82 (m, 4H), 1.94 to 2.00 (m, 4H), 2.04 to 2.12 (m, 2H), 2 .21 to 2.28 (m, 2H), 2.57 to 2.68 (m, 1H), 2.73 to 2.83 (m, 1H), 2.98 to 3.06 (m, 4H) 7.65 (q, J = 0.9 Hz, 1H), 8.02 (s, 1H), 8.28 (d, J = 1.9 Hz, 1H), 8.40 (d, J = 1. 9 Hz, 1H), 11.64 (brs, 1H).

2- (5-((1s, 4s) -4- (pyrrolidin-1-yl) cyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -4- (trifluoromethyl) thiazole ( I-85)

Compound (IIb-85) (54 mg, 0.10 mmol) in EtOH (2 mL) and 10% aqueous NaOH (1 mL) was refluxed for 90 min as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product (55 mg by LCMS (column LUNA 10 μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. ) To give (I-85) (22 mg, 0.05 mmol, 54%) as a white powder. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 1.60~1.73 (m, 4H), 1.75~1.84 (m, 4H), 1.91~2.01 (m, 2H), 2 .06 to 2.18 (m, 2H), 2.38 to 2.44 (m, 1H), 2.63 to 2.73 (m, 4H), 2.82 (tt, J = 3.9, 10.2 Hz, 1H), 7.55 (q, J = 0.8 Hz, 1H), 7.93 (s, 1H), 8.31 (d, J = 1.9 Hz, 1H), 8.39 ( d, J = 1.9 Hz, 1H), 11.44 (brs, 1H).

4-((1r, 4r) -4- (3- (thiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (I-89)

Compound (IIb-89) (44 mg, 0.09 mmol) in EtOH (2 mL) and 10% aqueous NaOH (1 mL) was refluxed for 90 min as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product (I-89) (28 mg, 0.07 mmol, 86%), light yellow powder did not require further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.42 to 1.55 (m, 2H), 1.64 to 1.77 (m, 2H), 2.06 to 2.19 (m, 4H), 2 .36 to 2.47 (m, 1H), 2.62 to 2.79 (m, 5H), 3.79 (t, J = 4.5 Hz, 2H), 7.26 (d, J = 3. 3 Hz, 1 H), 7.87 (d J = 3.3 Hz, 1 H), 7.94 (s, 1 H), 8.31 (br s, 1 H), 8.47 (br s, 1 H), 10. 03 (br s, 1H).

4-((1s, 4s) -4- (3- (thiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (I-90)

Compound (IIb-90) (86 mg, 0.17 mmol) in EtOH (2 mL) and 10% aqueous NaOH (1 mL) was refluxed for 90 min as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product (I-90) (58 mg, 0.16 mmol, 94%), light yellow powder did not require further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.56 to 1.67 (m, 2H), 1.69 to 1.78 (m, 2H), 2.03 to 2.16 (m, 4H), 2 .29 to 2.35 (m, 1H), 2.49 to 2.59 (m, 4H), 2.87 to 2.96 (m, 1H), 3.81 (t, J = 4.6 Hz, 2H), 7.28 (d, J = 3.3 Hz, 1H), 7.88 (d.J = 3.3 Hz, 1H), 7.97 (s, 1H), 8.37 (brs, 1H) ), 8.51 (br s, 1H), 10.36 (br s, 1H).

2-Methyl-4- (5-((1r, 4r) -4- (4-methylpiperazin-1-yl) cyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole (I -91)

Compound (IIb-91) (192 mg, 0.36 mmol) in EtOH (2 mL) and 10% aqueous NaOH (1 mL) was refluxed for 1 h as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product (I-91) (130 mg, 92%), white solid did not need further purification. ¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD several drops) δ 1.38 to 1.50 (q, J = 12.4 Hz, 2H), 1.54 to 1.66 (q, J = 11.6 Hz, 2H), 2.06 (d, J = 14.8 Hz, 4H), 2.29 (s, 3H), 2.36 to 2.75 (m, 10H), 2.77 (s, 3H), 7 .17 (s, 1H), 7.78 (s, 1H), 8.11 (s, 1H), 8.12 (s, 1H).

2-Methyl-4- (5-((1s, 4s) -4- (4-methylpiperazin-1-yl) cyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole (I -92)

Compound (IIb-92) (178 mg, 0.33 mmol) in EtOH (2 mL) and 10% aqueous NaOH (0.6 mL) was added as described in General Procedure A for 7-azaindole deprotection. Deprotected by refluxing for hours. The crude product (I-92) (111 mg, 84%), white solid did not require further purification. ¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD several drops) δ 1.54 to 1.73 (m, 4H), 1.92 to 2.07 (m, 4H), 2.31 (s, 3H), 2.44-2.71 (m, 5H), 2.76 (s, 3H), 2.80-2.89 (m, 1H), 2.94-3.02 (m, 4H), 7. 19 (s, 1H), 7.78 (s, 1H), 8.18 (d, J = 1.9 Hz, 1H), 8.19 (d, J = 1.9 Hz, 1H).

4-((1r, 4r) -4- (3- (2- (1-methylpiperidin-4-yl) thiazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) (Cyclohexyl) morpholine (I-94)

Compound (IIb-94) (48 mg, 0.079 mmol) in EtOH (2 mL) and 10% aqueous NaOH (0.6 mL) was prepared as described in General Procedure A for 7-azaindole deprotection. Deprotected by refluxing for minutes. The crude product was purified by PTLC using CHCl ₃ : MeOH: NH ₄ OH = 83: 15: 2 (v / v / v) as eluent to give (I-94) as a white solid. (19 mg, 51%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.41 to 1.52 (dq, J = 2.6, 12.2 Hz, 2H), 1.58 to 1.70 (dq, J = 2.2, 12) .6 Hz, 2H), 1.94 to 2.26 (m, 12H), 2.36 (s, 3H), 2.65 (t, J = 4.5 Hz, 4H), 2.97 to 3.04. (M, 2H), 3.04 to 3.13 (tt, J = 3.6, 11.4 Hz, 1H), 3.74 (t, J = 4.6 Hz, 4H), 7.22 (s, 1H), 7.83 (s, 1H), 8.18 (d, J = 1.9 Hz, 1H). 8.25 (d, J = 1.9 Hz, 1H), 10.32 (brs, NH, 1H).

4- (5-((1r, 4r) -4- (4-methylpiperazin-1-yl) cyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -2- (1-methyl Piperidin-4-yl) thiazole (I-96)

Compound (IIb-96) (44 mg, 0.071 mmol) in EtOH (2 mL) and 10% aqueous NaOH (0.57 mL) was added as described in General Procedure A for 7-azaindole deprotection. Deprotected by refluxing for minutes. The crude product was purified by PTLC using CHCl ₃ : MeOH: NH ₄ OH = 83: 15: 2 (v / v / v) as eluent to give (I-96) (19.5 mg, 57% ) Was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.43 to 1.55 (dq, J = 2.1, 12.1 Hz, 2H), 1.57 to 1.70 (dq, J = 1.9, 12) .6 Hz, 2H), 1.91 to 2.25 (m, 12H), 2.32 (s, 3H), 2.35 (s, 3H), 2.39 to 2.48 (tt, J = 3) .3, 12.2 Hz, 1H), 2.46 to 2.59 (m, 3H), 2.61 to 2.76 (m, 4H), 2.95 to 3.03 (m, 2H), 3 .04-3.12 (tt, J = 3.8, 11.5 Hz, 1H), 7.23 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 8.17 ( d, J = 2.0 Hz, 1H). 8.24 (d, J = 2.0 Hz, 1H), 10.33 (brs, NH, 1H).

2- (1-Methylpiperidin-4-yl) -4- (5-((1r, 4r) -4- (pyrrolidin-1-yl) cyclohexyl) -1H-pyrrolo [2,3-b] pyridine-3 -Yl) thiazole (I-98)

Compound (IIb-98) (57 mg, 0.097 mmol) in EtOH (2 mL) and 10% aqueous NaOH (0.39 mL) was prepared as described in General Procedure A for 7-azaindole deprotection. Deprotected by refluxing for minutes. The crude product was purified by PTLC using CHCl ₃ : MeOH: NH ₄ OH = 83: 15: 2 (v / v / v) as eluent to give (I-98) (21 mg, 48%). Obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.45 to 1.57 (dq, J = 2.0, 12.1 Hz, 2H), 1.59 to 1.71 (dq, J = 2.2, 12) .2 Hz, 2H), 1.79 to 1.87 (m, 4H), 1.91 to 2.08 (m, 4H), 2.10 to 2.24 (m, 7H), 2.35 (s) , 3H), 2.65 to 2.75 (m, 5H), 2.95 to 3.02 (m, 2H), 3.04 to 3.12 (tt, J = 3.8, 11.5 Hz, 1H), 7.23 (s, 1H), 7.84 (d, J = 1.6 Hz, 1H), 8.17 (d, J = 1.9 Hz, 1H). 8.26 (d, J = 2.0 Hz, 1H), 10.65 (brs, NH, 1H).

4- (4- (3- (2- (1-Methylpiperidin-4-yl) thiazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohex-3-enyl ) Morpholine (I-100)

Bromide (III-h) (0.70 g, 1.35 mmol), boronic acid (VIb-54) in EtOH (10 ml), toluene (10 ml) and 1.0 M Na ₂ CO ₃ solution (4.05 ml) ( 0.48 g, 1.62 mmol), lithium chloride (0.17 g, 4.06 mmol) and Pd (PPh ₃ ) ₂ Cl ₂ (0.095 g, 0.13 mmol), and general procedure A for the Suzuki reaction. And reacted under reflux for 72 hours. On aminosilica (Chromatorex NH, Fuji Silysia) using EtOAc: hexane (50:50 to 100: 0, v / v gradient) followed by EtOAc: MeOH (100: 0 to 90:10, v / v gradient) The crude product was purified by SGC on to give (I-100) as a light red solid (0.27 g, 43%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.59 to 1.71 (m, 1H), 1.91 to 2.03 (m, 2H), 2.09 to 2.30 (m, 6H), 2.35 (s, 3H), 2.43 to 2.52 (m, 1H), 2.58 to 2.74 (m, 7H), 2.94 to 3. 12 (m, 3H), 3.78 (t, J = 4.6 Hz, 4H), 6.06 to 6.10 (m, 1H), 7.23 (s, 1H), 7.85 (d, J = 2.1 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 11.27 (br s, NH, 1H) .

4- (4- (3- (2- (1-Methylpiperidin-4-yl) thiazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohex-3-enyl ) -1,4-oxazepane (I-101) -4- (4- (3- (2- (1-methylpiperidin-4-yl) thiazol-4-yl) -1- (phenylsulfonyl) -1H- Preparation of pyrrolo [2,3-b] pyridin-5-yl) cyclohex-3-enyl) -1,4-oxazepane (IIa-101) See 4-((1r, 4r) -4- (3- ( 2- (1-Methylpiperidin-4-yl) thiazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepane (I-102)

Compound (IIb-102) (20 mg, 0.032 mmol) in EtOH (1 mL) and 10% aqueous NaOH (0.13 mL) was prepared as described in General Procedure A for 7-azaindole deprotection. Deprotected by refluxing for minutes. The crude product was purified by PTLC using CHCl ₃ : MeOH: NH ₄ OH = 83: 15: 2 (v / v / v) as eluent to give (I-102) (8 mg, 51%). Obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.46 to 1.57 (q, J = 11.1 Hz, 2H), 1.59 to 1.71 (q, J = 12.3 Hz, 2H), 1. 90-2.11 (m, 8H), 2.13-2.26 (m, 4H), 2.36 (s, 3H), 2.62 to 2.81 (m, 2H), 2.85 2.94 (m, 4H), 2.99 to 3.13 (m, 3H), 3.79 (t, J = 4.2 Hz, 2H), 3.83 (t, J = 5.9 Hz, 2H) ), 7.24 (s, 1H), 7.81 (d, J = 1.9 Hz, 1H), 8.18 (d, J = 1.7 Hz, 1H), 8.24 (d, J = 1) .9 Hz, 1H), 9.66 (brs, NH, 1H).

4-((1r, 4r) -4- (3- (2- (1-methylpyrrolidin-2-yl) thiazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) (Cyclohexyl) morpholine (I-107)

Compound (IIb-107) (53 mg, 0.09 mmol) in EtOH (1 mL) and 10% aqueous NaOH (0.36 mL) was added as described in General Procedure A for 7-azaindole deprotection. Deprotected by refluxing for minutes. The crude product was purified by PTLC using CH ₂ Cl ₂ : MeOH = 9: 1 (v / v) as eluent to give (I-107) (12 mg, 30%) as a white solid. . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.41 to 1.52 (dq, J = 2.2, 12.2 Hz, 2H), 1.59 to 1.70 (dq, J = 2.2, 12) .2 Hz, 2H), 1.82 to 2.03 (m, 4H), 2.11 (t, J = 4.5 Hz, 4H), 2.35 to 2.46 (m, 3H), 2.48. (S, 3H), 2.62-2.73 (m, 5H), 3.29 (tt, J = 1.8, 8.1 Hz, 1H), 3.78 (t, J = 4.4 Hz, 4H), 3.79-3.83 (dd, J = 6.2, 8.9 Hz, 1H), 7.30 (s, 1H), 7.85 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 8.25 (d, J = 1.9 Hz, 1H), 9.95 (brs, NH, 1H).

4-((1s, 4s) -4- (3- (2- (1-methylpyrrolidin-2-yl) thiazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) (Cyclohexyl) morpholine (I-108)

Compound (IIb-108) (33 mg, 56 μmol) in EtOH (1 mL) and 10% aqueous NaOH (0.36 mL) was refluxed for 20 minutes as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product was purified by PTLC using CH ₂ Cl ₂ : MeOH = 9: 1 (v / v) as eluent to give (I-108) (9.4 mg, 37%) as a white solid. Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.54 to 1.64 (m, 2H), 1.66 to 1.73 (m, 2H), 1.83 to 1.91 (m, 1H), 1 .95-2.10 (m, 6H), 2.27-2.32 (m, 1H), 2.39-2.46 (m, 2H), 2.48 (s, 3H), 2.50 ˜2.55 (br s, 4H), 2.82 to 2.91 (m, 1H), 3.26 to 3.32 (m, 1H), 3.78 (t, J = 4.5 Hz, 4H) ), 3.80 to 3.84 (dd, J = 6.4, 8.8 Hz, 1H), 7.30 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 8 .24 (d, J = 1.8 Hz, 1H), 8.29 (d, J = 1.9 Hz, 1H), 9.72 (brs, NH, 1H).

4- (5-((1r, 4r) -4- (4-methylpiperazin-1-yl) cyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -2- (1-methyl Pyrrolidin-2-yl) thiazole (I-109)

Compound (IIb-109) (31 mg, 51 μmol) in EtOH (2 mL) and 10% aqueous NaOH (0.51 mL) was refluxed for 20 min as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product was purified by PTLC using CH ₂ Cl ₂ : MeOH = 8: 2 (v / v) as eluent to give (I-109) (17 mg, 71%) as a white solid. . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.44-1.56 (q, J = 111.2 Hz, 2H), 1.59-1.70 (q, J = 12.6 Hz, 2H), 1. 83 to 1.92 (m, 1H), 1.93 to 2.2.03 (m, 2H), 2.04 to 2.17 (m, 5H), 2.34 (s, 3H), 2. 39 to 2.48 (m, 2H), 2.48 (s, 3H), 2.47 to 2.62 (br m, 5H), 3.29 (t, J = 8.6 Hz, 1H), 3 .79 to 3.84 (dd, J = 6.2, 8.6 Hz, 1H), 7.30 (s, 1H), 7.83 (d, J = 0.8 Hz, 1H), 8.15 ( d, J = 1.8 Hz, 1H), 8.23 (d, J = 1.9 Hz, 1H), 9.70 (brs, NH, 1H).

4- (5-((1s, 4s) -4- (4-methylpiperazin-1-yl) cyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -2- (1-methyl Pyrrolidin-2-yl) thiazole (I-110)

Compound (IIb-110) (23 mg, 38 μmol) in EtOH (2 mL) and 10% aqueous NaOH (0.15 mL) was refluxed for 20 min as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product was purified by PTLC using CH ₂ Cl ₂ : MeOH = 8: 2 (v / v) as eluent to give (I-110) (19.5 mg, 57%) as a white solid. Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.56 to 1.65 (m, 2H), 1.67 to 1.75 (m, 2H), 1.83 to 1.93 (m, 1H), 1 .95-2.12 (m, 9H), 2.34 (s, 3H), 2.39-2.65 (br m, 8H), 2.48 (s, 3H), 2.83-2. 92 (m, 1H), 3.29 (tt, J = 1.6, 8.1 Hz, 1H), 3.79 to 3.84 (dd, J = 6.2, 8.6 Hz, 1H), 7 .31 (s, 1H), 7.83 (d, J = 1.3 Hz, 1H), 8.23 (d, J = 1.7 Hz, 1H), 8.29 (d, J = 1.9 Hz, 1H), 9.70 (brs, NH, 1H).

2- (1-Methylpyrrolidin-2-yl) -4- (5-((1r, 4r) -4- (pyrrolidin-1-yl) cyclohexyl) -1H-pyrrolo [2,3-b] pyridine-3 -Yl) thiazole (I-111)

Compound (IIb-111) (23 mg, 40 μmol) in EtOH (1 mL) and 10% aqueous NaOH (0.16 mL) was refluxed for 30 min as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product was purified by PTLC using CHCl ₃ : MeOH: NH ₄ OH = 83: 15: 2 (v / v / v) as eluent to give (I-111) (10 mg, 57%). Obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.46 to 1.57 (q, J = 12.0 Hz, 2H), 1.59 to 1.72 (q, J = 12.8 Hz, 2H), 1. 81 to 1.96 (m, 6H), 1.96 to 2.07 (m, 5H), 2.16 to 2.25 (m, 3H), 2.40 to 2.49 (m, 1H), 2.48 (s, 3H), 2.64 to 2.73 (m, 4H), 3.29 (t, J = 8.0 Hz, 1H), 3.79 to 3.84 (dd, J = 6) .3, 8.7 Hz, 1H), 7.31 (s, 1H), 7.83 (d, J = 2.1 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 8 .25 (d, J = 1.6 Hz, 1H), 9.56 (brs, NH, 1H).

4-((1r, 4r) -4- (3- (2- (1-methylpyrrolidin-2-yl) thiazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) (Cyclohexyl) -1,4-oxazepane (I-113)

Compound (IIb-113) (46 mg, 76 μmol) in EtOH (1 mL) and 10% aqueous NaOH (0.30 mL) was refluxed for 20 minutes as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product was purified by PTLC using CH ₂ Cl ₂ : MeOH = 85: 15 (v / v) as eluent to give (I-113) (12 mg, 34%) as a white solid. . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.47 to 1.58 (q, J = 11.6 Hz, 2H), 1.60 to 1.71 (q, J = 12.6 Hz, 2H), 1. 84 to 2.04 (m, 5H), 2.05 to 2.12 (br d, J = 11.0 Hz, 4H), 2.38 to 2.48 (m, 2H), 2.48 (s, 3H), 2.62-2.72 (m, 1H), 2.73-2.83 (m, 1H), 2.87-2.96 (m, 4H), 3.29 (tt, J = 1.5, 8.1 Hz, 1H), 3.78 to 3.82 (m, 1H), 3.80 (t, J = 4.6 Hz, 2H), 3.84 (t, J = 6.1 Hz) , 2H), 7.30 (s, 1H), 7.84 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 1.9 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1 ), 9.92 (br s, NH, 1H).

4-((1s, 4s) -4- (3- (2- (1-methylpyrrolidin-2-yl) thiazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) (Cyclohexyl) -1,4-oxazepane (I-114)

Compound (IIb-114) (30 mg, 50 μmol) in EtOH (1 mL) and 10% aqueous NaOH (0.30 mL) was refluxed for 20 minutes as described in General Procedure A for 7-azaindole deprotection. By deprotection. The crude product was purified by PTLC using CH ₂ Cl ₂ : MeOH = 85: 15 (v / v) as eluent to give (I-114) (7.5 mg, 32%) as a white solid Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.65 to 1.83 (m, 4H), 1.89 to 2.04 (m, 8H), 2.12 (m, 3H), 2.38 to 2 .48 (m, 1H), 2.48 (s, 3H), 2.89 to 3.00 (br s, 6H), 3.29 (tt, J = 2.5, 7.6 Hz, 1H), 3.78 to 3.85 (m, 4H), 7.34 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 8.29 (s, 1H), 8.30 ( d, J = 1.8 Hz, 1H), 9.63 (brs, 1H).

4-((1r, 4r) -4- (3- (thiazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepane (I-116 )

Bromide (IXb-75) (120 mg, 0.24 mmol), N, N-dicyclohexylmethylamine (52 mg, 0.27 mmol), 4- (tributylstannyl) thiazole (138 mg, 0.37 mmol), dichlorobis (di-tert) A mixture of -butylphosphinite-kP) paradate (2-) 2 hydrogen (7 mg, 0.01 mmol) in DMF (3 mL) was stirred at 135 ° C. for 19 hours. The mixture was then cooled to room temperature and partitioned between EtOAc (20 mL) and saturated aqueous NaHCO ₃ (10 mL). The aqueous layer was extracted with EtOAc (2 × 15 mL). The combined organic solution was dried (MgSO ₄ ), filtered and concentrated. The orange residue was purified by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. Purification gave azaindole (I-116) (24.1 mg, 26%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.51 to 1.67 (m, 4H), 2.03 to 2.16 (m, 6H), 2.57 to 2.64 (m, 1H), 3 .04-3.12 (m, 5H), 3.82 (t, J = 6.0 Hz, 2H), 3.84-3.87 (m, 2H), 6.44 (d, J = 3. 4 Hz, 1H), 7.31 (d, J = 3.4 Hz, 1H), 7.80 (d, J = 1.9 Hz, 1H), 8.01 (s, 1H), 8.05 (d, J = 1.9 Hz, 1H), 10.29 (brs, 1H).

4-((1r, 4r) -4- (3- (4-methylthiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepane ( I-117)

Compound (IIb-117) (38.3 mg, 0.07 mmol) in EtOH (4 mL) and 10% aqueous NaOH (0.70 mL) was prepared as described in General Procedure A for 7-azaindole deprotection. And deprotection by refluxing for 1.5 hours. The crude product (I-117) (24.4 mg, 85%), a light yellow powder, did not require further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.45 to 1.56 (m, 2H), 1.60 to 1.71 (m, 2H), 1.86 to 1.94 (m, 2H), 2 .00 to 2.11 (m, 4H), 2.54 (d, J = 1.0 Hz, 3H), 2.64 to 2.76 (m, 2H), 2.83 to 2.92 (m, 4H), 3.74 to 3.79 (m, 2H), 3.83 (t, J = 6.0 Hz, 2H), 6.78 (d, J = 1.0 Hz, 1H), 7.93 ( s, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 10.84 (br s, 1H).

4-((1r, 4r) -4- (3- (thiazol-5-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepane (I-118 )

Compound (IIb-118) (containing (XXVIIb-75)) (15.1 mg, 0.02 mmol) in EtOH (4 mL) and 10% aqueous NaOH (0.50 mL) was deprotected of 7-azaindole. Was deprotected by stirring at 90 ° C. for 40 minutes as described in General Procedure A. The crude product was purified by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. Azaindole (I-118) (6.1 mg, 77%) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.52 to 1.71 (m, 4H), 2.04 to 2.16 (m, 6H), 2.63 to 2.72 (m, 1H), 3 0.03 to 3.09 (m, 5H), 3.82 to 3.87 (m, 4H), 7.55 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 8 0.06 (s, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.77 (s, 1H), 10.60 (brs, 1H).

4-((1r, 4r) -4- (3- (thiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepane (I-119 )

Crude stannane (XXVIII-75) (250 mg, ca. 0.30 mmol), 2-bromothiazole (88 mg, 0.53 mmol), tri-O-tolylphosphine (21 mg, 0.07 mmol), dichlorobis (acetonitrile) palladium (II) (9 mg, 0.04 mmol) and toluene (2 mL) were reacted at 85 ° C. for 20 hours using a modified general procedure B for Stille reaction. The reaction mixture was filtered and concentrated. LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent followed by aminosilica plate The remaining brown oil was purified by PTLC on (Chromatorex NH, Fuji Silysia) to give (I-119) (4.1 mg, 2.3%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.46 to 1.56 (m, 2H), 1.60 to 1.72 (m, 2H), 1.87 to 2.09 (m, 6H), 2 .64 to 2.81 (m, 2H), 2.88 to 2.92 (m, 4H), 3.78 to 3.79 (m, 2H), 3.82 (t, J = 6.0 Hz, 2H), 7.24 (d, J = 3.3 Hz, 1H), 7.85 (d, J = 3.4 Hz, 1H), 7.88 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H).

4-((1r, 4r) -4- (3- (2-methoxythiazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (I-120)

Concentration of compound (IIb-120) (289.00 mg, purity 60.00%, 0.34 mmol) over 7 minutes using concentrated aqueous HCl (2.00 ml, 24.00 mmol) in MeOH (20.00 mL) 7 Deprotection according to general procedure B of azaindole deprotection. The crude product was purified by LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. To give (I-120) (51.00 mg, 38%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.49 (qd, J = 12.3, 2.4 Hz, 2H), 1.65 (qd, J = 12.8, 2.2 Hz, 2H), 2. 05-2.18 (m, 5H), 2.35-2.46 (m, 2H), 2.60-2.75 (m, 5H), 3.79 (t, J = 4.4 Hz, 4H) ) 4.20 (s, 3H), 6.76 (s, 1H), 7.78 (s, 1H), 8.17 (d, J = 1.9 Hz, 1H), 8.24 (d, J = 1.9 Hz, 1H), 9.81 (bs, 1H).

3- (5-Methyl-1,3-thiazol-2-yl) -5- [trans-4- (1,4-oxazepan-4-yl) cyclohexyl] -1H-pyrrolo [2,3-b] pyridine (I-121)

Compound (IIb-121) (18.3 mg, 0.03 mmol) in EtOH (4 mL) and 10% aqueous NaOH (0.70 mL) was prepared as described in General Procedure A for 7-azaindole deprotection. And deprotection by stirring at 90 ° C. for 1 hour. The usual workup gave crude azaindole (I-121) (10.2 mg, 75%) as a pale yellow powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.42 to 1.73 (m, 4H), 1.85 to 1.94 (m, 2H), 1.98 to 2.09 (m, 4H), 2 .52 (s. 3H), 2.62 to 2.73 (m, 2H), 2.80 to 2.89 (m, 4H), 3.73 to 3.78 (m, 2H), 3.82 (T, J = 5.8 Hz, 2H), 7.47 (d, J = 1.0 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 10.15 (brs, NH).

5- [trans-4- (1,4-oxazepan-4-yl) cyclohexyl] -3- (2-pyrrolidin-1-yl-1,3-thiazol-4-yl) -1H-pyrrolo [2,3 -B] pyridine (I-122)

Compound (IIb-122) (30.1 mg, 0.05 mmol) in EtOH (5 mL) and 10% aqueous NaOH (0.70 mL) was prepared as described in General Procedure A for 7-azaindole deprotection. And deprotection by stirring at 90 ° C. for 1 hour. The usual workup gave crude azaindole (I-122) (19.3 mg, 84%) as a pale yellow powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.43 to 1.54 (m, 2H), 1.57 to 1.69 (m, 2H), 1.70 to 1.80 (m, 2H), 1 .85 to 1.93 (m, 2H), 2.05 to 2.10 (m, 6H), 2.59 to 2.72 (m, 2H), 2.81 to 2.89 (m, 4H) 3.53 to 3.58 (m, 4H), 3.73 to 3.77 (m, 2H), 3.82 (t, J = 5.9 Hz, 2H), 6.56 (s, 1H) 7.74 (d, J = 2.3 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 9.29 ( brs, NH).

3- (4,5-Dimethyl-1,3-thiazol-2-yl) -5- [trans-4- (1,4-oxazepan-4-yl) cyclohexyl] -1H-pyrrolo [2,3-b Pyridine (I-123)

Compound (IIb-123) (70.3 mg, 0.13 mmol) in EtOH (5 mL) and 10% aqueous NaOH (0.70 mL) was prepared as described in General Procedure A for 7-azaindole deprotection. The mixture was deprotected by stirring at 90 ° C. for 1.3 hours. The usual workup gave crude azaindole (I-123) (44.4 mg, 83%) as a pale yellow powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.43 to 1.56 (m, 2H), 1.59 to 1.72 (m, 2H), 1.84 to 1.94 (m, 2H), 1 .99 to 2.10 (m, 4H), 2.41 (s, 6H), 2.63 to 2.74 (m, 2H), 2.82 to 2.89 (m, 4H), 3.73 ˜3.78 (m, 2H), 3.82 (t, J = 6.0 Hz, 2H), 7.85 (d, J = 2.1 Hz, 1H), 8.25 (d, J = 2. 1 Hz, 1H), 8.33 (d, J = 2.1 Hz, 1H), 10.50 (brs, NH).

3- (2-Methoxy-1,3-thiazol-4-yl) -5- [trans-4- (1,4-oxazepan-4-yl) cyclohexyl] -1H-pyrrolo [2,3-b] pyridine (I-124)

Compound (IIb-124) (94.4 mg, 0.17 mmol) in EtOH (5 mL) and 10% aqueous NaOH (0.70 mL) was prepared as described in General Procedure A for 7-azaindole deprotection. And deprotection by stirring at 90 ° C. for 1 hour. The usual workup gave crude azaindole (I-124) (55.8 mg, 78%) as a pale yellow powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.42 to 1.55 (m, 2H), 1.57 to 1.69 (m, 2H), 1.84 to 1.93 (m, 2H), 1 .98 to 2.11 (m, 4H), 2.60 to 2.73 (m, 2H), 2.80 to 2.89 (m, 4H), 3.73 to 3.77 (m, 2H) 3.82 (t, J = 6.0 Hz, 2H), 4.18 (s, 3H), 6.73 (s, 1H), 7.77 (d, J = 2.1 Hz, 1H), 8 .14 (d, J = 2.1 Hz, 1H), 8.24 (d, J = 2.1 Hz, 1H), 10.07 (brs, NH).

3- (2-Ethoxy-1,3-thiazol-4-yl) -5- [trans-4- (1,4-oxazepan-4-yl) cyclohexyl] -1H-pyrrolo [2,3-b] pyridine (I-125)

Compound (IIb-125) (82.3 mg, 0.14 mmol) in EtOH (5 mL) and 10% aqueous NaOH (0.70 mL) was prepared as described in General Procedure A for 7-azaindole deprotection. The mixture was deprotected by stirring at 90 ° C. for 1.5 hours. The usual workup gave crude azaindole (I-124) (24.8 mg, 40%) as a pale yellow powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.46 to 1.55 (m, 2H), 1.50 (t, J = 7.1 Hz, 3H), 1.57 to 1.69 (m, 2H) 1.85 to 1.93 (m, 2H), 1.98 to 2.11 (m, 4H), 2.60 to 2.72 (m, 2H), 2.81 to 2.88 (m, 4H), 3.73 to 3.78 (m, 2H), 3.82 (t, J = 6.0 Hz, 2H), 4.56 (q, J = 7.1, 14.2 Hz, 2H), 6.72 (s, 1H), 7.76 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 10.16 (brs, NH).

4- (5-Cyclopentenyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -2- (1-methylpiperidin-4-yl) thiazole (IIa-1)

Bromide (III-h) (267 mg, 0.52 mmol), cyclopent-1-enylboronic acid (80 mg, 0 ml) in EtOH (2 ml), toluene (2 ml) and 1.0 M Na ₂ CO ₃ solution (1.0 ml). .68 mmol), lithium chloride (70 mg, 1.65 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (30 mg, 43 μmol) were reacted under reflux for 2 hours using the general procedure A for Suzuki reaction. . The crude product (89 mg) was purified by SGC using CH ₂ Cl ₂ : MeOH 19: 1 (v / v) to give (IIa-1) (213 mg, 0.42 mmol, 81%) as a foam. Got as. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.80 to 2.17 (m, 8H), 2.27 (s, 3H), 2.45 to 2.52 (m, 2H), 2.65 to 2 .72 (m, 2H), 2.87 to 3.03 (m, 3H), 6.18 (quintage, J = 2.2 Hz, 1H), 7.27 (s, 1H), 7.40 (T, J = 7.8 Hz, 2H), 7.49 (tt, J = 1.3, 7.4 Hz, 1H), 8.05 (s, 1H), 8.11 to 8.17 (m, 2H), 8.24 (d, J = 2.1 Hz, 1H), 8.53 (d, J = 2.1 Hz, 1H).

Preparation of (IIb-11)-(I-11) Reference 4- (5-cyclohexenyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -N, N- Diethylthiazol-2-amine (IIa-12)

Bromide (III-i) (253 mg, ca. 0.45 mmol), pinacol cyclohexenylboronate in EtOH (1.5 ml), toluene (1.5 ml) and 1.0 M Na ₂ CO ₃ solution (0.75 ml) Ester (150 mg, 0.72 mmol), lithium chloride (80 mg, 1.89 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (50 mg, 71 μmol) were refluxed using general procedure A for the Suzuki reaction for 3 hours. Reacted below. The crude product (344 mg) was purified by SGC using CH ₂ Cl ₂ to give (IIa-12) (105 mg, 213 μmol, 47%) as a foam. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.31 (t, J = 7.1 Hz, 6H), 1.65 to 1.73 (m, 2H), 1.78 to 1.85 (m, 2H) 2.21 to 2.28 (m, 2H), 2.42 to 2.49 (m, 2H), 3.58 (q, J = 7.2 Hz, 4H), 6.13 to 6.18 ( m, 1H), 6.67 (s, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.57 (tt, J = 1.4, 7.5 Hz, 1H), 8. 11 (s, 1H), 8.20 (d, J = 7.8 Hz, 2H), 8.48 (d, J = 2.2 Hz, 1H), 8.51 (d, J = 2.2 Hz, 1H) ).

Preparation of (IIb-18)-(I-18) See 2- (1-methylpiperidin-4-yl) -4- (1- (phenylsulfonyl) -5- (1,4-dioxaspiro [4.5] Decan-8-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole (IIb-23)

Using the general procedure for the hydrogenation of 7-azaindole using 20% Pd (OH) ₂ / C (Degussa form, 0.40 g) in MeOH (30 mL) -EtOAc (30 mL) over 20 h. (IIa-36) (1.08 g, 1.87 mmol) was hydrogenated. The reaction mixture was then filtered through celite and washed with copious amounts of CH ₂ Cl ₂ : MeOH (1: 1). The solvent was removed to give (IIb-23) (0.76 g, 70%) as a white foam. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.58 to 1.92 (m, 10H), 2.22 to 2.35 (m, 2H), 2.41 to 2.53 (m, 2H), 2 .62 (s, 3H), 2.65 to 2.74 (m, 2H), 3.22 to 3.30 (m, 2H), 3.97 (s, 4H), 7.38 (s, 1H) ), 7.44 to 7.49 (m, 2H), 7.53 to 7.60 (m, 1H), 8.11 (s, 1H), 8.12 (s, 1H), 8.19 to 8.22 (m, 2H), 8.35 (d, J = 2.0 Hz, 1H).

2- (1-Methylpiperidin-4-yl) -4- (1- (phenylsulfonyl) -5- (1,4-dioxaspiro [4.5] decan-8-yl) -1H-pyrrolo [2,3 See also the preparation of -b] pyridin-3-yl) thiazole (IIb-23)-(I-23) 2- (5-cyclohexenyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] Pyridin-3-yl) thiazole (IIa-24)

EtOH (1 ml), toluene (1 ml) and 1.0M of solution _{of Na} 2 CO ₃ (0.5 ml) of Bromide (III-j) (190mg, 0.45mmol), cyclohexenyl boronic acid pinacol ester (120 mg, 0 .56 mmol), lithium chloride (80 mg, 1.89 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (25 mg, 36 μmol) were reacted under reflux using the general procedure A for Suzuki reaction for 3.5 hours. I let you. The crude product (brown oil, 385 mg) was purified by SGC using CH ₂ Cl ₂ to give (IIa-24) (139 mg, 0.33 mmol, 73%) as a foam. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.67 to 1.74 (m, 2H), 1.80 to 1.87 (m, 2H), 2.22 to 2.29 (m, 2H), 2 .45 to 2.51 (m, 2H), 6.16 to 6.20 (m, 1H), 7.35 (d, J = 3.3 Hz, 1H), 7.53 (t, J = 7. 6 Hz, 2H), 7.62 (tt, J = 1.5, 7.5 Hz, 1H), 7.91 (d, J = 3.3 Hz, 1H), 8.24-8.29 (m, 3H) ), 8.44 (d, J = 2.2 Hz, 1H), 8.56 (d, J = 2.2 Hz, 1H).

(4- (1- (Phenylsulfonyl) -5- (1,4-dioxaspiro [4.5] decan-8-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole-2 -Yl) (piperidin-1-yl) methanone (IIb-25)

Using the general procedure for hydrogenation of 7-azaindole using 20% Pd (OH ₂ ) / C (Degussa form, 40 mg) in MeOH (5 mL) -CH ₂ Cl ₂ (5 mL) over 20 h. Compound (IIa-37) (115 mg, 0.18 mmol or less) was hydrogenated. The reaction mixture was then filtered through celite and concentrated to give the crude reduction product (IIb-25) (103 mg, 0.17 mmol, 96%) as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.48 to 2.20 (m, 14H), 3.76 to 3.78 (m, 2H), 3.93 ( s, 4H), 4.31 to 4.40 (m, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7. 59 (s, 1H), 8.04 (s, 1H), 8.14-8.21 (m, 3H), 8.31 (s, 1H).

2- (5-cyclohexyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole (IIb-26)

Using the general procedure for hydrogenation of 7-azaindole over 4 days with 20% Pd (OH ₂ ) / C (Degussa form, 30 mg) in MeOH (4 mL) -CH ₂ Cl ₂ (2 mL) Compound (IIa-24) (114 mg, 0.27 mmol) was hydrogenated. The reaction mixture was then filtered through celite, washed with MeOH: CH ₂ Cl ₂ and concentrated to give the crude reduction product as a brown oil (92 mg). The oil was purified by SGC using CH ₂ Cl ₂ as the eluent to give (IIb-26) (55 mg, 0.13 mmol, 48%) as a foam. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.16-1.50 (m, 5H), 1.66-1.87 (m, 5H), 2.60 (tt, J 3.3, 11.9 Hz) , 1H), 7.26 (d, J = 3.3 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.53 (tt, J = 1.4, 7.4 Hz, 1H), 7.82 (d, J = 3.3 Hz, 1H), 8.15-8.20 (m, 3H), 8.30 (d, J = 2.1 Hz, 1H), & 8.34 ( d, J = 2.1 Hz, 1H).

Ethyl 4- (5- (4,4-dimethylcyclohexa-1,5-dienyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole-2-carboxy Rate (IIa-35)

Bromide (III-a) (300 mg, 0.61 mmol or less), 4,4-dimethyl-cyclohexa-1 in EtOH (2 ml), toluene (2 ml) and 1.0 M Na ₂ CO ₃ solution (1.0 ml) , 5-dienylboronic acid pinacol ester (163 mg, 0.70 mmol), lithium chloride (80 mg, 1.89 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (80 mg, 0.11 mmol) were added to a general solution for the Suzuki reaction. Reacted under reflux using Procedure A for 2 hours. The crude product (430 mg) was purified by SGC using AcOEt: hexane 1: 4 (v / v) to give (IIa-35) (112 mg, 0.22 mmol, 35%) as a foam. . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.00 (s, 6H), 1.42 (t, J = 7.1 Hz, 3H), 2.24 (d, J = 4.7 Hz, 2H), 4 .45 (q, J = 7.1 Hz, 2H), 5.69 (dd, J = 0.8, 9.6 Hz, 1H), 5.95 to 5.99 (m, 1H), 6.24 ( dd, J = 1.7, 9.7 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.51 (tt, J = 1.2, 7.8 Hz, 1H), 7 .67 (s, 1H), 8.14-8.23 (m, 4H), 8.47 (d, J = 2.1 Hz, 1H).

2- (1-Methylpiperidin-4-yl) -4- (1- (phenylsulfonyl) -5- (1,4-dioxaspiro [4.5] dec-7-en-8-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole (IIa-36)

Bromide (III-h) (109 mg, 0.28 mmol), boronic acid pinacol ester (VIb-36) in EtOH (1 ml), toluene (1 ml) and 1.0 M Na ₂ CO ₃ solution (0.5 ml) ( 75 mg, 0.28 mmol), lithium chloride (35 mg, 0.83 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (25 mg, 36 μmol) under reflux for 1 h using the general procedure A for Suzuki reaction. Reacted. The crude product (186 mg) was purified by SGC using CH ₂ Cl ₂ : MeOH 23: 2 (v / v) to give (IIa-36) (148 mg, 0.26 mmol, 92%) as a foam. Got as. ¹ H NMR (400 MHz, CDCl ₃ ) δ ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.91 to 2.04 (m, 4H), 2.10 to 2.24 (m, 4H), 2.34 ( s, 3H), 2.47 to 2.52 (m, 2H), 2.67 to 2.73 (m, 2H), 2.95 to 3.11 (m, 3H), 4.04 (s, 4H), 5.98 to 6.02 (m, 1H), 7.34 (s, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.56 (t, J = 7. 4 Hz, 1 H), 8.13 (s, 1 H), 8.19 to 8.22 (m, 2 H), 8.27 (d, J = 2.2 Hz, 1 H), 8.53 (d, J = 2.2 Hz, 1 H).

(4- (1- (Phenylsulfonyl) -5- (1,4-dioxaspiro [4.5] dec-7-en-8-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl) ) Thiazol-2-yl) (piperidin-1-yl) methanone (IIa-37)

EtOH (1 ml), toluene (1 ml) and 1.0M of solution _{of Na} 2 CO ₃ (0.5 ml) of Bromide (III-c) (96mg, 0.18mmol), boronic acid pinacol ester (VIb-36) ( 65 mg, 0.24 mmol), lithium chloride (30 mg, 0.71 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (25 mg, 36 μmol) under reflux for 1 h using the general procedure A for Suzuki reaction. Reacted. The crude product (221 mg) was purified by SGC using AcOEt: hexane 1: 1 (v / v) to give (IIa-37) (115 mg, crude yield> 100%) as a foam. . ¹ H NMR (400 MHz, CDCl ₃ ) δ ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.71 to 1.81 (m, 6H), 1.96 (t, J = 6.5 Hz, 2H), 2. 48 to 2.52 (m, 2H), 2.67 to 2.74 (m, 2H), 3.76 to 3.82 (m, 2H), 4.05 (s, 4H), 4.35 to 4.41 (m, 2H), 5.98 to 6.02 (m, 1H), 7.50 (t, J = 7.9 Hz, 2H), 7.60 (tt, J = 1.3, 7) .5 Hz, 1 H), 7.67 (s, 1 H), 8.14 (s, 1 H), 8.22 to 8.26 (m, 2 H), 8.32 (d, J = 2.3 Hz, 1 H) ), 8.55 (d, J = 2.3 Hz, 1H).

Ethyl 4- (5- (4-methylcyclohex-1-enyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole-2-carboxylate (IIa- 38)

Bromide (III-a) (600 mg, 1.22 mmol), 4-methyl-cyclohex-1-enylboron in EtOH (5 ml), toluene (5 ml) and 1.0 M Na ₂ CO ₃ solution (2.0 ml) Acid pinacol ester (220 mg, 1.57 mmol), lithium chloride (180 mg, 4.24 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (75 mg, 0.11 mmol) were prepared using general procedure A for the Suzuki reaction. For 1 hour under reflux. The crude product was purified by SGC using AcOEt: hexane 1: 2 (v / v) to give (IIa-38) (540 mg, 0.99 mmol, 81%) as a foam. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.04 (d, J 6.4 Hz, 3H), 1.38 to 1.59 (m, 4H), 1.72 to 2.00 (m, 3H), 2.29-2.40 (m, 1H), 2.46-2.61 (m, 2H), 4.54 (q, J = 7.1 Hz, 2H), 6.11-6.19 (m , 1H), 7.50 (t, J = 7.9 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.75 (s, 1H), 8.22 to 8.35. (M, 4H), 8.55 (d, J = 2.1 Hz, 1H).

Ethyl 4- (5-cyclopentenyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole-2-carboxylate (IIa-39)

Bromide (III-a) (480 mg, 0.98 mmol), cyclopent-1-enylboronic acid (130 mg, 1 ml) in EtOH (4 ml), toluene (4 ml) and 1.0 M Na ₂ CO ₃ solution (2.0 ml). .16 mmol), lithium chloride (140 mg, 3.30 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (60 mg, 86 μmol) were reacted under reflux for 1.5 h using the general procedure A for Suzuki reaction. I let you. The crude product (548 mg) was purified by SGC using AcOEt: hexane 1: 4 (v / v) to give (IIa-39) (374 mg, 0.78 mmol, 80%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.51 (t, J = 7.1 Hz, 3H), 2.08 (quintage, J = 7.5 Hz, 2H), 2.56 to 2.63 ( m, 2H), 2.77 to 2.84 (m, 2H), 4.55 (q, J = 7.1 Hz, 2H), 6.30 (quintage, J = 2.1 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.60 (tt, J = 1.3, 7.4 Hz, 1H), 7.74 (s, 1H), 8.23 to 8.30 (M, 3H), 8.36 (d, J = 2.1 Hz, 1H), 8.65 (d, J = 2.1 Hz, 1H).

Preparation of (IIa-40)-(I-11) Reference Ethyl 4- (5-cyclohexenyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazol-2- Carboxylate (IIa-41)

Bromide (III-a) (668 mg, 1.36 mmol), cyclohex-1-enylboronic acid (200 mg, in EtOH (4 ml), toluene (4 ml) and 1.0 M Na ₂ CO ₃ solution (2.0 ml) 1.59 mmol), lithium chloride (165 mg, 3.89 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (100 mg, 0.14 mmol) were added under reflux for 1 h using the general procedure A for Suzuki reaction. Reacted. The crude product (1.18 g) was purified by SGC using AcOEt: hexane 1: 4 (v / v) to give (IIa-41) (600 mg, 1.22 mmol, 89%) as a solid. . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.50 (t, J = 7.1 Hz, 3H), 1.66 to 1.73 (m, 2H), 1.78 to 1.86 (m, 2H) 2.21 to 2.28 (m, 2H), 2.43 to 2.50 (m, 2H), 4.54 (q, J = 7.1 Hz, 2H), 6.14 to 6.17 ( m, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.59 (tt, J = 1.3, 7.4 Hz, 1H), 7.75 (s, 1H), 8. 22-8.29 (m, 3H), 8.30 (d, J = 2.1 Hz, 1H), 8.54 (d, J = 2.1 Hz, 1H).

Ethyl 4- (5-cyclohexyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole-2-carboxylate (IIb-42)

Using the general procedure for hydrogenation of 7-azaindole using 20% Pd (OH ₂ ) / C (Degussa form, 100 mg) in MeOH (10 mL) over 4 days, compound (IIa-41) (600 mg 1.22 mmol). The reaction mixture was then filtered through celite and concentrated to give the crude reduction product (IIb-42) (650 mg, crude yield> 100%) as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.27 to 1.56 (m, 7H), 1.76 to 1.97 (m, 6H), 2.64 to 2.73 (m, 1H), 4 .55 (q, J = 7.1 Hz, 2H), 7.51 (t, J = 7.7 Hz, 2H), 7.60 (tt, J = 1.2, 7.5 Hz, 1H), 7. 74 (s, 1H), 8.19 (d, J = 2.1 Hz, 1H), 8.23 to 8.29 (m, 3H), 8.39 (d, J = 2.1 Hz, 1H).

Ethyl 4- (1- (phenylsulfonyl) -5- (1,4-dioxaspiro [4.5] dec-7-en-8-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl ) Thiazole-2-carboxylate (IIa-43)

Bromide (III-a) (3.00 g, 6.09 mmol), boronic acid pinacol ester in EtOH (15.2 ml), toluene (15.2 ml) and 1.0 M Na ₂ CO ₃ solution (15.2 ml) (VIb-36) (1.94g, 7.31mmol), lithium chloride (0.77g, 18.27mmol), and _{Pd (PPh 3) 2 Cl 2} (0.43g, 0.61mmol) and the Suzuki reaction The reaction was carried out under reflux using general procedure A for 3 hours. The crude product (221 mg) was purified by SGC using AcOEt: hexane (gradient elution) to give (IIa-43) (2.30 g, 68%) as a light brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.49 (t, J = 7.2 Hz, 3H), 1.95 (t, J = 6.5 Hz, 2H), 2.48 to 2.51 (m, 2H), 2.69 to 2.76 (m, 2H), 4.04 (s, 4H), 4.53 (q, J = 7.2 Hz, 2H), 6.01 to 6.04 (m, 1H), 7.46 to 7.51 (m, 2H), 7.55 to 7.60 (m, 1H), 7.73 (s, 1H), 8.21 to 8.24 (m, 2H) 8.27 (s, 1H), 8.33 (d, J = 2.1 Hz, 1H), 8.56 (d, J = 2.1 Hz, 1H).

Ethyl 4- (1- (phenylsulfonyl) -5- (1,4-dioxaspiro [4.5] decan-8-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole-2 -Carboxylate (IIb-44)

Using the general procedure for hydrogenation of 7-azaindole using 20% Pd (OH ₂ ) / C (Degussa form, 0.29 g) in MeOH (15 mL) and EtOAc (41.7 mL) over 5 days. Compound (IIa-43) (2.30 g, 4.17 mmol) was hydrogenated. The reaction mixture was then filtered through celite and concentrated to give the crude reduction product (IIb-44) (2.13 g, 92%) as a yellow foam. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.50 (t, J = 7.1 Hz, 3H), 1.68 to 1.78 (m, 2H), 1.81 to 1.93 (m, 6H) 2.68-2.79 (m, 2H), 4.00 (s, 4H), 4.53 (q, J = 7.1 Hz, 2H), 7.47-7.53 (m, 2H) 7.56 to 7.61 (m, 1H), 7.73 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.23 to 8.26 (m, 2H) 8.29 (s, 1H), 8.41 (d, J = 2.1 Hz, 1H).

Ethyl 4- (5- (4-oxocyclohexyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole-2-carboxylate (IIb-45)

Compound (IIb-44) (2.13 g, 3.85 mmol) was dissolved in THF (38.5 mL). 7M HCl (1.28 mL) was then added in one portion at room temperature. The reaction was stirred at room temperature overnight. It was then quenched by adding saturated aqueous NaHCO ₃ (100 mL) over 10 minutes. The mixture was extracted with EtOAc (3 × 100 mL). The combined extracts were dried over MgSO ₄ and concentrated to give the product (IIb-45) as a yellow foam (1.92 g, 98%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.49 (t, J = 7.2 Hz, 3H), 1.96 to 2.09 (m, 2H), 2.23 to 2.31 (m, 2H) 2.49-2.59 (m, 4H), 3.21 (tt, J = 3.3 and 12.2 Hz, 1H), 4.53 (q, J = 7.2 Hz, 2H), 7. 47-7.53 (m, 2H), 7.58-7.62 (m, 1H), 7.73 (s, 1H), 8.22-8.25 (m, 2H), 8.26 ( s, 1H), 8.29 (d, J = 2.1 Hz, 1H), 8.43 (d, J = 2.1 Hz, 1H).

Methyl 4- (5-((1s, 4s) -4-morpholinocyclohexyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole-2-carboxylate (IIb -46) and methyl 4- (5-((1r, 4r) -4-morpholinocyclohexyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazol-2- Carboxylate (IIb-47)

Ketone (IIb-45) (0.50 g, 0.98 mmol), morpholine (0.51 g, 5.88 mmol), 1.25 M HCl / MeOH (1.57 mL, 1.96 mmol) in anhydrous methanol (9.8 mL). ) And NaCNBH ₃ (0.12 g, 1.96 mmol) were reacted according to General Procedure A for reductive amination. The crude product was purified by PTLC using CH ₂ Cl ₂ : MeOH = 10: 1 (v / v) to give methyl esters (IIb-46) (138 mg, 25%) and (IIb-47) (147 mg 26%) as a colorless oil.

Data for cis isomer (IIb-46): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.45 to 1.68 (m, 4H), 1.92 to 2.05 (m, 4H), 2.43 To 2.53 (br m, 4H), 2.66 to 2.74 (m, 1H), 2.77 to 2.88 (m, 1H), 3.72 to 3.79 (m, 4H), 4.06 (s, 3H), 7.46-7.54 (m, 2H), 7.55-7.60 (m, 1H), 7.75 (s, 1H), 8.20-8. 28 (m, 4H), 8.43 (d, J = 1.7 Hz, 1H).

Data of trans isomer (IIb-47): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.37 to 1.62 (m, 4H), 1.97 to 2.14 (m, 4H), 2.30 ~ 2.41 (m, 1H), 2.58-2.69 (m, 5H), 3.75 (t, J = 4.4 Hz, 4H), 4.06 (s, 3H), 7.46 To 7.51 (m, 2H), 7.55 to 7.60 (m, 1H), 7.73 (s, 1H), 8.19 (d, J = 1.9 Hz, 1H), 8.20 ~ 8.25 (m, 2H), 8.26 (s, 1H), 8.36 (s, 1H).

4- (4- (3- (2-Methylthiazol-4-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohex-3-enyl) morpholine (IIa-54)

EtOH (10ml), toluene (10ml) and 1.0M of solution _{of Na} 2 CO ₃ (4.0 ml) of Bromide (III-k) (1.07g, 2.45mmol), boronic acid pinacol ester (VIb-54 ) (863 mg, 2.94 mmol), LiCl (312 mg, 7.36 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (86 mg, 0.12 mmol) using the general procedure A for Suzuki reaction for 2 hours. The reaction was carried out under reflux. The crude product (1.65 g; dark brown oil) was purified by SGC using AcOEt: CH ₂ Cl ₂ : MeOH (50: 50: 0 to 45:45:10; v / v gradient elution). (IIa-54) (1.15 g, 2.21 mmol, 90%) was obtained as a light brown foam. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.57 to 1.69 (m, 1H), 2.16 to 2.31 (m, 2H), 2.43 to 2.73 (m, 8H), 2 .83 (s, 3H), 3.79 (t, J = 4.6 Hz, 2H), 6.07-6.12 (m, 1H), 7.32 (s, 1H), 7.49 (t , J = 7.8 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 8.17 (s, 1H), 8.17 to 8.21 (m, 3H), 8.53. (D, J = 2.1 Hz, 1H).

4-((1r, 4r) -4- (3- (2-methylthiazol-4-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) Morpholine (IIb-55) 4-((1s, 4s) -4- (3- (2-methylthiazol-4-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine- 5-yl) cyclohexyl) morpholine (IIb-56)

Using the general procedure for hydrogenation of 7-azaindole using EtOH (3 mL) and 20% Pd (OH ₂ ) / C (Degussa form, 50 mg) in AcOEt (3 mL) over 3 days, compound (IIa -54) (140 mg, 0.27 mmol) was hydrogenated. The reaction mixture was then filtered through celite, washed with ethanol (50 mL) and concentrated to give the crude reduction product as an oil (133 mg). The oil was purified by SGC using AcOEt: CH ₂ Cl ₂ : MeOH (gradient from 50: 50: 0 to 45:45:10 v / v). The first eluent was (IIb-56) (57 mg, 0.11 mmol, 41%) and then (IIb-55) (62 mg, 0.12 mmol, 44%).

(IIb-55) data: ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.38-1.65 (m, 4H), 1.99-2.14 (m, 4H), 2.30-2. 41 (m, 1H), 2.58 to 2.71 (m, 4H), 2.82 (s, 3H), 3.77 (t, J = 4.6 Hz, 2H), 7.31 (s, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.58 (tt, J = 1.5, 7.4 Hz, 1H), 8.12 (d, J = 2.1 Hz, 1H) ), 8.16 (s, 1H), 8.21 to 8.26 (m, 2H), 8.36 (d, J = 2.1 Hz, 1H).

(IIb-56) data: ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.51 to 1.69 (m, 4H), 1.93 to 2.09 (m, 4H), 2.26 to 2. 31 (m, 1H), 2.43 to 2.56 (m, 4H), 2.77 to 2.87 (m, 4H), 3.76 (t, J = 4.6 Hz, 2H), 7. 32 (s, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.58 (tt, J = 1.5, 7.5 Hz, 1H), 8.16 (s, 1H), 8.22 to 8.26 (m, 2H), 8.20 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H).

4- (5-Cyclohexenyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -2-methylthiazole (IIa-57)

EtOH (2 ml), toluene (2 ml) and 1.0M of solution _{of Na} 2 CO ₃ (0.72 mL) of Bromide (III-k) (208mg, 0.48mmol), 2- cyclohexenyl -4,4,5 , 5-Tetramethyl-1,3,2-dioxaborolane (130 mg, 0.62 mmol), LiCl (61 mg, 1.44 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (17 mg, 0.02 mmol) were added to the Suzuki reaction. Reacted under reflux using general procedure A for 2 hours. The crude product (0.38 g; dark brown oil) was purified by SGC using AcOEt: CH ₂ Cl ₂ : MeOH (50: 50: 0 to 45:45:10; v / v gradient elution). (IIa-57) (183 mg, 0.42 mmol, 88%) was obtained as a foam. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.66 to 1.74 (m, 2H), 1.79 to 1.87 (m, 2H), 2.21 to 2.29 (m, 2H), 2 .42-2.50 (m, 2H), 2.82 (s, 3H), 6.12-6.16 (m, 1H), 7.32 (s, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.58 (tt, J = 1.5, 7.5 Hz, 1H), 8.17 (s, 1H), 8.21 to 8.26 (m, 3H), 8 .53 (d, J = 2.2 Hz, 1H).

4- (5-cyclohexyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -2-methylthiazole (IIb-58)

Using the general procedure for hydrogenation of 7-azaindole using 18% EtOH (1 mL) and 20% Pd (OH ₂ ) / C (Degussa form, 50 mg) in THF (1 mL) over 18 h, compound (IIa -57) (135 mg, 0.31 mmol) was hydrogenated. The reaction mixture was then filtered through celite, washed with ethanol (50 mL) and concentrated to give the crude reduction product (IIb-58) as an oil (133 mg, 0.30 mmol, 97%), which was further purified. There was no need. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.17 to 1.47 (m, 5H), 1.66 to 1.88 (m, 5H), 2.53 to 2.62 (m, 1H), 2 .73 (s, 3H), 7.19 (s, 1H), 7.40 (t, J = 7.7 Hz, 2H), 7.49 (tt, J = 1.5, 7.4 Hz, 1H) 8.02 (d, J = 2.1 Hz, 1H), 8.08 (s, 1H), 8.13 to 8.17 (m, 2H), 8.28 (d, J = 2.0 Hz, 1H).

4-((1r, 4r) -4- (1- (tert-butyldimethylsilyl) -3- (thiazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) Preparation of Morpholine (IIb-59)-(I-59) Reference 4-((1r, 4r) -4- (1- (tert-butyldimethylsilyl) -3- (thiazol-5-yl) -1H-pyrrolo Preparation of [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (IIb-60)-(I-60) See 4-((1r, 4r) -4- (1- (tert-butyldimethylsilyl) ) -3- (4-Methylthiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (IIb-61)-(I-61) Reference 4- ((1r, 4r)- -(1- (tert-butyldimethylsilyl) -3- (5-methylthiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (IIb-62)- Preparation of (I-62) Reference 4-((1r, 4r) -4- (1- (tert-butyldimethylsilyl) -3- (2-ethoxythiazol-4-yl) -1H-pyrrolo [2,3 -B] Preparation of pyridin-5-yl) cyclohexyl) morpholine (IIb-63)-(I-63) See 4-((1r, 4r) -4- (1- (tert-butyldimethylsilyl) -3- Preparation of (4,5-dimethylthiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (IIb-64)-(I-64) See 2- (1 -(Fe Rusulfonyl) -5- (1,4-dioxaspiro [4.5] dec-7-en-8-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -4- (trifluoro Methyl) thiazole (IIa-65)

Bromide (III-l) (1.26 g, 2.58 mmol), boronic acid (VIb) in EtOH (8 mL), toluene (8 mL) and 1.0 M Na ₂ CO ₃ solution (3.87 mL, 3.87 mmol). −36) (690 mg, 2.58 mmol), LiCl (330 mg, 7.74 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (110 mg, 0.15 mmol) using the general procedure A for the Suzuki reaction 3 The reaction was allowed to react under reflux for hours The crude product (2.64 g; dark brown oil) was purified by SGC using AcOEt: hexane = 1: 1 (v / v) and a light brown foam was obtained. yield, which was further purified by trituration with _{Et 2 O, (IIa-65} ) as a white powder ^{(1.26g, 2.30mmol, 89%)} . 1 H _{MR (400MHz, CDCl 3) δ} 1.99 (t, J = 6.3Hz, 2H), 2.51~2.56 (m, 2H), 2.71~2.78 (m, 2H), 4 0.06 (s, 4H), 6.05 to 6.09 (m, 1H), 7.54 (t, J = 7.7 Hz, 2H), 7.64 (tt, J = 1.5, 7. 5 Hz, 1H), 7.76 (q, J = 0.8 Hz, 1H), 8.25-8.30 (m, 2H), 8.32 (s, 1H), 8.53 (d, J = 2.2 Hz, 1H), 8.61 (d, J = 2.2 Hz, 1H).

2- (1- (phenylsulfonyl) -5- (1,4-dioxaspiro [4.5] decan-8-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -4- ( Trifluoromethyl) thiazole (IIb-66)

Using the general procedure for hydrogenation of 7-azaindole over 3 days using EtOH (5 mL) and 20% Pd (OH ₂ ) / C (Degussa form, 100 mg) in THF (5 mL), compound (IIa -65) (1.26 g, 2.30 mmol) was hydrogenated. The reaction mixture was then filtered through celite, washed with ethanol (100 mL) and concentrated to give the reduced product (IIb-66) (1.11 g, 2.06 mmol, 88%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.70 to 2.00 (m, 8H), 2.73 to 2.82 (m, 1H), 4.02 (s, 4H), 6.05 to 6 .09 (m, 1H), 7.54 (t, J = 7.8 Hz, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.76 (s, 1H), 8.26 ˜8.32 (m, 2H), 8.33 (s, 1H), 8.37 (d, J = 2.1 Hz, 1H), 8.45 (d, J = 2.1 Hz, 1H).

4- (1- (phenylsulfonyl) -3- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexanone (IIb-67)

6.0 M aqueous HCl (7 mL, 42 mmol) was added to a stirred solution of (IIb-66) (1.13 g, 2.06 mmol) in THF (20 mL) and the reaction mixture was stirred at room temperature for 2 hours. The solution was then slowly added to saturated NaHCO ₃ solution (100 mL) and the mixture was extracted with AcOEt (3 × 100 mL). The combined organic extracts were dried over MgSO ₄ and concentrated to give (IIb-67) as a clear oil (1.04 g, 2.06 mmol, 100%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.98 to 2.12 (m, 2H), 2.24 to 2.33 (m, 1H), 2.54 to 2.63 (m, 4H), 3 .25 (tt, J = 3.2, 12.1 Hz, 1H), 7.56 (t, J = 7.7 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7. 77 (s, 1H), 8.27 to 8.31 (m, 2H), 8.33 (s, 1H), 8.47 (s, 2H).

4- (4- (1- (phenylsulfonyl) -3- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohex-3 -Enyl) morpholine (IIa-68)

Bromide (III-l) (455 mg, 0.93 mmol), boronic acid (VIb-54) in EtOH (4 mL), toluene (4 mL) and 1.0 M Na ₂ CO ₃ solution (2.0 mL, 2.0 mmol). ) (360 mg, 1.23 mmol), LiCl (120 mg, 2.83 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (50 mg, 0.07 mmol) were added for 16 h using the general procedure A for Suzuki reaction. The reaction was carried out under reflux. The crude product (676 mg; dark brown oil) was purified by SGC using AcOEt: CH ₂ Cl ₂ : MeOH (50: 50: 0 to 45:45:10, v / v gradient) to give impurities Which gave further product (378 mg) which was further purified by trituration with Et ₂ O (5 mL) to give (IIa-68) as a white powder (285 mg, 0.50 mmol, 53% ). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.59 to 1.71 (m, 1H), 2.18 to 2.33 (m, 2H), 2.45 to 2.73 (m, 8H), 3 .79 (t, J = 4.6 Hz, 4H), 6.11 to 6.16 (m, 1H), 7.54 (t, J = 7.8 Hz, 2H), 7.64 (t, J = 7.5 Hz, 1 H), 7.76 (s, 1 H), 8.26-8.30 (m, 2 H), 8.32 (s, 1 H), 8.51 (d, J = 2.1 Hz, 1H), 8.58 (d, J = 2.1 Hz, 1H).

4-((1r, 4r) -4- (1- (phenylsulfonyl) -3- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrrolo [2,3-b] pyridine-5- Yl) cyclohexyl) morpholine (IIb-69) 4-((1s, 4s) -4- (1- (phenylsulfonyl) -3- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrrolo [ 2,3-b] pyridin-5-yl) cyclohexyl) morpholine (IIb-70)

Using the general procedure for hydrogenation of 7-azaindole over 4 days using 20% Pd (OH ₂ ) / C (Degussa form, 100 mg) in EtOH (5 mL) and THF (5 mL), compound (IIa -68) (285 mg, 0.50 mmol) was hydrogenated. The reaction mixture was then filtered through celite, washed with ethanol (100 mL) and concentrated to give the reduced product (261 mg) as an oil. CH ₂ Cl _2: hexane (1: 2 to 2: 1, v / v gradient of) SGC (NH silica, loaded with Fuji Silysia) to use by, purified oil, cis isomer (IIb-70) (58 mg 0.10 mmol, 20%). Next eluted the trans isomer (IIb-69) (78 mg, 0.14 mmol, 27%).

Data of trans isomer (IIb-69): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.39 to 1.66 (m, 4H), 2.00 to 2.15 (m, 4H), 2.32 ~ 2.42 (m, 1H), 2.59-2.74 (m, 5H), 3.77 (t, J = 4.6 Hz, 4H), 7.54 (t, J = 7.8 Hz, 2H), 7.64 (tt, J = 1.5, 7.5 Hz, 1H), 7.76 (q, J = 0.8 Hz, 1H), 8.25-8.30 (m, 2H), 8.32 (s, 1H), 8.38 (d, J = 2.1 Hz, 1H), 8.41 (d, J = 2.1 Hz, 1H).

Data for cis isomer (IIb-70): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.52-1.68 (m, 4H), 1.95-2.11 (m, 4H), 2.26 -2.33 (m, 1H), 2.43-2.57 (m, 4H), 2.80-2.91 (m, 1H), 3.72-3.84 (m, 4H), 6 .11-6.16 (m, 1H), 7.55 (t, J = 7.8 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.76 (s, 1H) 8.25-8.33 (m, 3H), 8.46 (d, J = 2.1 Hz, 1H), 8.51 (d, J = 2.1 Hz, 1H).

2-Methyl-4- (1- (phenylsulfonyl) -5- (1,4-dioxaspiro [4.5] dec-7-en-8-yl) -1H-pyrrolo [2,3-b] pyridine- 3-yl) thiazole (IIa-71)

Bromide (III-k) (1.87 g, 4.31 mmol), boronic acid (VIb) in EtOH (10 mL), toluene (10 mL) and 1.0 M Na ₂ CO ₃ solution (5.2 mL, 5.2 mmol) −36) (1.66 g, 6.23 mmol), LiCl (550 mg, 12.92 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (150 mg, 0.22 mmol) were added to the general procedure A for the Suzuki reaction. And reacted under reflux for 2 hours. The crude product (3.61 g; dark brown oil) was purified by SGC using AcOEt: CH ₂ Cl ₂ : hexane = 1: 1: 2 (v / v / v) to give a light brown foam (2.09 g) which was further purified by trituration with Et ₂ O (25 mL) to give (IIa-71) (1.71 g, 3.46 mmol, 80%) as a white powder. Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.97 (t, J = 6.5 Hz, 2H), 2.50 to 2.54 (m, 2H), 2.70 to 2.76 (m, 2H) 2.82 (s, 3H), 4.06 (s, 4H), 6.00 to 6.04 (m, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.58 (Tt, J = 1.5, 7.5 Hz, 1H), 8.17 (s, 1H), 8.21 to 8.25 (m, 2H), 8.28 (d, J = 2.1 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H).

2-methyl-4- (1- (phenylsulfonyl) -5- (1,4-dioxaspiro [4.5] decan-8-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl) Thiazole (IIb-72)

Using the general procedure for hydrogenation of 7-azaindole over 3 days using 20% Pd (OH ₂ ) / C (Degussa form, 250 mg) in EtOH (10 mL) and THF (10 mL), compound (IIa -71) (1.71 g, 3.47 mmol) was hydrogenated. The reaction mixture was then filtered through celite, washed with ethanol (200 mL) and concentrated to give (IIb-72) (1.67 g, 3.37 mmol, 97%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.70-1.96 (m, 8H), 2.70-2.80 (m, 1H), 2.83 (s, 3H), 4.02 (s , 4H), 7.32 (s, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.59 (tt, J = 1.5, 7.4 Hz, 1H), 8.14. (D, J = 2.0 Hz, 1H), 8.18 (s, 1H), 8.22 to 8.26 (m, 2H), 8.39 (d, J = 2.0 Hz, 1H).

4- (3- (2-Methylthiazol-4-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexanone (IIb-73)

To a stirred solution of (IIb-72) (1.71 g, 3.45 mmol) in THF (50 mL) was added 6.0 M aqueous HCl (15 mL, 90 mmol) and the reaction mixture was stirred at room temperature for 2 h. The solution was then slowly added to saturated aqueous NaHCO ₃ (200 mL) and the mixture was extracted with AcOEt (3 × 150 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated to give (IIb-73) (1.37 g, 3.03 mmol, 88%) as a clear oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.98 to 2.10 (m, 2H), 2.24 to 2.33 (m, 2H), 2.52 to 2.61 (m, 4H), 2 .83 (s, 3H), 3.22 (tt, J 3.4, 12.2 Hz, 1H), 7.32 (s, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.60 (tt, J = 1.5, 7.5 Hz, 1H), 8.16 (s, 1H), 8.22 to 8.27 (m, 3H), 8.42 (d, J = 2) .1Hz, 1H).

2-Methyl-4- (1- (phenylsulfonyl) -5-((1r, 4r) -4- (pyrrolidin-1-yl) cyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl ) Thiazole (IIb-74)

Ketone (IIb-73) (371 mg, 0.82 mmol), pyrrolidine (500 mg, 7.03 mmol), and 1.25 M HCl / MeOH (2.50 mL, 3.13 mmol) in anhydrous methanol (2 mL) were added to MeOH ( NaCNBH ₃ (100 mg was added at -20 ° C. as a solution in 2 mL), were reacted according to the general procedure a for the reductive amination 1.59 mmol). Crude product by SGC using AcOEt: CH ₂ Cl ₂ : MeOH: Et ₃ N as eluent (47: 47: 5: 1 to 42: 42: 15: 1; v / v / v / v gradient) The product (380 mg) was purified to give (IIb-74) as a white powder (177 mg, 0.35 mmol, 43%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.54 to 1.67 (m, 2H), 1.70 to 1.83 (m, 2H), 1.98 to 2.09 (m, 6H), 2 .07 to 2.28 (m, 2H), 2.68 to 2.80 (m, 2H), 2.82 (s, 3H), 3.05 to 3.14 (m, 4H), 7.33 (S, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.59 (tt, J = 1.5, 7.5 Hz, 1H), 8.15 (d, J = 2. 1 Hz, 1H), 8.16 (s, 1H), 8.20-8.24 (m, 3H), 8.34 (d, J = 2.1 Hz, 1H). The cis isomer was also formed in the reaction but was not isolated.

4-((1r, 4r) -4- (3- (2-methylthiazol-4-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepane (IIb-75) and 4-((1s, 4s) -4- (3- (2-methylthiazol-4-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepane (IIb-76)

Ketone (IIb-73) (603 mg, 1.34 mmol), perhydro-1,4-oxazepine hydrochloride (1.47 g, 10.68 mmol), iPr ₂ NEt (690 mg, 5.34 mmol) in anhydrous methanol (8 mL) Was reacted with NaBH ₃ CN (168 mg, 2.67 mmol) added at −20 ° C. as a solution in MeOH (5 mL) according to General Procedure A for reductive amination. The crude product (877 mg, oil) was purified by SGC using AcOEt: MeOH (98: 2 to 85:15, v / v gradient) as eluent. The first to elute was the cis isomer (IIb-76) (223 mg, 0.42 mmol, 31%) as a clear oil. Further elution gave the trans isomer (IIb-75) (343 mg, 0.64 mmol, 49%) as a solid.

Data of trans isomer (IIb-75): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.45 to 1.58 (m, 2H), 1.59 to 1.74 (m, 2H), 1.89 -2.17 (m, 6H), 2.65 (tt, J = 3.6, 11.7 Hz, 1H), 2.72-2.84 (m, 1H), 2.83 (s, 3H) 2.88-2.99 (m, 4H), 3.76-3.88 (m, 4H), 7.31 (s, 1H), 7.49 (t, J = 7.7 Hz, 2H) 7.58 (tt, J = 1.5, 7.4 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 8.16 (s, 1H), 8.21-8. 25 (m, 3H), 8.35 (d, J = 2.1 Hz, 1H).

Data for cis isomer (IIb-76): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.60 to 2.14 (m, 10H), 2.82 (s, 3H), 2.83 to 2.99 (M, 6H), 3.75 to 3.87 (m, 4H), 7.34 (s, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.59 (tt, J = 1.5, 7.5 Hz, 1H), 8.17 (s, 1H), 8.22 to 8.26 (m, 3H), 8.44 (d, J = 2.1 Hz, 1H).

4- (4- (3- (4- (1-Methylpiperidin-4-yl) thiazol-2-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl ) Cyclohex-3-enyl) morpholine (IIa-77)

Bromide (III-n) (778 mg, 1.50 mmol), boronic acid (VIb-54) (510 mg, in EtOH (4 mL), toluene (4 mL) and 1.0 M Na ₂ CO ₃ solution (2 mL, 2 mmol). 1.73 mmol), LiCl (191 mg, 4.51 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (50 mg, 0.07 mmol) were reacted under reflux for 16 hours using the general procedure A for Suzuki reaction. I let you. The crude product (1.14 g) by SGC using AcOEt: CH ₂ Cl ₂ : MeOH (47.5: 47: 5: 5 to 42.5: 42.5: 15, gradient v / v / v). ; dark brown oil) was purified to give an almost pure material 592 mg, which was further purified by trituration with _{Et 2 O (10mL), (} IIa-77) (577mg, 0.96mmol 64%) as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.57 to 1.73 (m, 2H), 1.83 to 1.98 (m, 2H), 2.10 to 2.33 (m, 6H), 2 .38 (s, 3H), 2.45 to 2.55 (m, 1H), 2.57 to 2.73 (m, 6H), 2.79 to 2.91 (m, 1H), 2.98 To 3.09 (m, 2H), 3.80 (t, J = 4.6 Hz, 2H), 6.09 to 6.13 (m, 1H), 6.92 (s, 1H), 7.51 (T, J = 7.7 Hz, 2H), 7.61 (tt, J = 7.4, 1.5 Hz, 1H), 8.22 to 8.28 (m, 3H), 8.47 (d, J = 2.2 Hz, 1H), 8.55 (d, J = 2.2 Hz, 1H).

4-((1r, 4r) -4- (3- (4- (1-methylpiperidin-4-yl) thiazol-2-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] Pyridin-5-yl) cyclohexyl) morpholine (IIb-78) and 4-((1s, 4s) -4- (3- (4- (1-methylpiperidin-4-yl) thiazol-2-yl)- 1- (Phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (IIb-79)

Using the general procedure for hydrogenation of 7-azaindole using EtOH (10 mL) and 20% Pd (OH ₂ ) / C (Degussa form, 100 mg) in THF (10 mL) over 3 days, compound (IIa -77) (577 mg, 0.96 mmol) was hydrogenated. The reaction mixture was then filtered through celite, washed with ethanol (100 mL) and concentrated to give the reduced product (535 mg) as an oil. The oil was purified by SGC using CH ₂ Cl ₂ : MeOH: Et ₃ N (10: 0: 0.05 to 8: 2: 0.05, v / v / v gradient) to give the cis isomer (IIb-79) (149 mg, about 80% purity, 0.20 mmol, 21%) was obtained. The next eluting was the trans isomer (IIb-78) (276 mg, about 80% purity, 0.36 mmol, 38%).

Data of trans isomer (IIb-78): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.42-1.79 (m, 4H), 1.89-2.34 (m, 6H), 2.40 ˜2.80 (m, 10H), 3.03 to 3.17 (m, 6H), 3.711 to 3.91 (m, 4H), 6.96 (s, 1H), 7.52 (t , J = 7.6 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 8.22 to 8.29 (m, 3H), 8.35 to 8.40 (m, 2H) .

Data for cis isomer (IIb-79): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.26-1.59 (m, 4H), 1.76-1.99 (m, 6H), 2.03 To 2.13 (m, 4H), 2.18 to 2.23 (m, 1H), 2.29 (s, 3H), 2.36 to 2.46 (m, 4H), 2.71 to 2 .81 (m, 2H), 2.89 to 2.98 (m, 2H), 3.67 (t, J = 4.5 Hz, 4H), 6.83 (s, 1H), 7.43 (t , J = 7.7 Hz, 2H), 7.52 (tt, J = 7.4, 1.5 Hz, 1H), 8.12-8.19 (m, 3H), 8.33-8.37 ( m, 2H).

4-((1r, 4r) -4- (1- (phenylsulfonyl) -3- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrrolo [2,3-b] pyridine-5- Yl) cyclohexyl) -1,4-oxazepane (IIb-80) and 4-((1s, 4s) -4- (1- (phenylsulfonyl) -3- (4- (trifluoromethyl) thiazol-2-yl) ) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepane (IIb-81)

To ketone (IIb-67) (250 mg, 0.49 mmol), perhydro-1,4-oxazepine hydrochloride (400 mg, 3.96 mmol), iPr ₂ NEt (256 mg, 1.98 mmol) in anhydrous methanol (6 mL). NaBH ₃ CN (62 mg, 0.99 mmol) added at −20 ° C. as a solution in MeOH (4 mL) was reacted according to General Procedure A for reductive amination. The crude product (356 mg, oil) by SGC using AcOEt: CH ₂ Cl ₂ : MeOH (49: 49: 2 to 42.5: 42.5: 15, v / v / v gradient) as eluent Was purified. The first to elute was the cis isomer (IIb-81) (74 mg, 0.13 mmol, 25%). Further elution gave the trans isomer (IIb-80) (97 mg, 0.16 mmol, 33%) as a solid.

Data of trans isomer (IIb-80): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.46-1.68 (m, 4H), 1.92-2.00 (m, 2H), 2.01 To 2.12 (m, 4H), 2.63 to 2.82 (m, 2H), 2.87 to 2.96 (m, 4H), 3.79 (t, J = 4.6 Hz, 2H) 3.84 (t, J = 6.0 Hz, 2H), 7.54 (t, J = 7.7 Hz, 2H), 7.64 (tt, J = 1.5, 7.5 Hz, 1H), 7.76 (q, J = 0.8 Hz, 1H), 8.26-8.30 (m, 2H), 8.32 (s, 1H), 8.38 (d, J = 2.1 Hz, 1H) ), 8.41 (d, J = 2.1 Hz, 1H).

Data for cis isomer (IIb-81): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.58 to 1.75 (m, 4H), 1.84 to 1.99 (m, 4H), 2.01 To 2.12 (m, 2H), 2.77 to 2.96 (m, 6H), 3.77 (t, J = 4.9 Hz, 2H), 3.83 (t, J = 5.9 Hz, 2H), 7.55 (t, J = 7.8 Hz, 2H), 7.64 (tt, J = 1.5, 7.5 Hz, 1H), 7.75 (q, J = 0.8 Hz, 1H) ), 8.26-8.32 (m, 3H), 8.48 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H).

2- (5-((1r, 4r) -4- (4-methylpiperazin-1-yl) cyclohexyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -4- (trifluoromethyl) thiazole (IIb-82) and 2- (5-((1s, 4s) -4- (4-methylpiperazin-1-yl) cyclohexyl) -1- (phenylsulfonyl) -1H -Pyrrolo [2,3-b] pyridin-3-yl) -4- (trifluoromethyl) thiazole (IIb-83)

Ketone (IIb-67) (250 mg, 0.49 mmol) in anhydrous methanol (6 mL), 1.25 M HCl in MeOH (1.60 mL, 2.00 mmol), and N-methyl-piperazine (396 mg, 3.96 mmol) ) Was reacted with NaBH ₃ CN (62 mg, 0.99 mmol) added at −20 ° C. as a solution in MeOH (4 mL) according to General Procedure A for reductive amination. The crude product (356 mg, oil) by SGC using AcOEt: CH ₂ Cl ₂ : MeOH (49: 49: 2 to 42.5: 42.5: 15, v / v / v gradient) as eluent Was purified. The first to elute was the cis isomer (IIb-83) (40 mg, 0.07 mmol, 14%) as a clear oil. Further elution gave the trans isomer (IIb-82) (93 mg, 0.16 mmol, 32%) as a solid.

Data of trans isomer (IIb-82): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.54-1.66 (m, 4H), 2.03-2.11 (m, 2H), 2.13 ˜2.20 (m, 2H), 2.48 (s, 3H), 2.65 to 3.00 (m, 10H), 3.03 to 3.02 (m, 1H), 7.54 (t , J = 7.8 Hz, 2H), 7.64 (tt, J = 7.4 Hz, 1H), 7.76 (q, J = 0.8 Hz, 1H), 8.25-8.30 (m, 3H), 8.31 (s, 1H), 8.37 (d, J = 2.0 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H).

Data for cis isomer (IIb-83): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.20-1.26 (m, 1H), 1.51-1.68 (m, 4H), 1.95 To 2.09 (m, 4H), 2.28 to 2.37 (m, 5H), 2.38 to 2.73 (m, 6H), 2.81 to 2.90 (m, 1H), 7 .56 (t, J = 7.7 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.76 (s, 1H), 8.26 to 8.31 (m, 3H) 8.46 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H).

2- (1- (phenylsulfonyl) -5-((1r, 4r) -4- (pyrrolidin-1-yl) cyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -4- (Trifluoromethyl) thiazole (IIb-84) and 2- (1- (phenylsulfonyl) -5-((1s, 4s) -4- (pyrrolidin-1-yl) cyclohexyl) -1H-pyrrolo [2,3 -B] pyridin-3-yl) -4- (trifluoromethyl) thiazole (IIb-85)

Ketone (IIb-67) (250 mg, 0.49 mmol) in anhydrous methanol (6 mL), 1.25 M HCl in MeOH (1.60 mL, 2.00 mmol), and pyrrolidine (284 mg, 3.99 mmol) in MeOH. NaBH ₃ CN (63 mg, 1.00 mmol) added at −20 ° C. as a solution in (4 mL) was reacted according to General Procedure A for reductive amination. The crude product (300 mg, oil) was purified by SGC using CHCl ₃ : MeOH: NH ₄ OH = 93: 6: 1 (v / v / v). The first to elute was the cis isomer (IIb-85) (54 mg, 0.10 mmol, 19%) as a clear oil. Further elution gave several mixed fractions (which were discarded) and the trans isomer (IIb-84) (23 mg, 0.04 mmol, 8%) as a solid.

Data of trans isomer (IIb-84): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.43-1.58 (m, 4H), 1.75-1.85 (m, 4H), 1.89 To 1.97 (m, 2H), 2.09 to 2.23 (m, 3H), 2.45 to 2.53 (m, 1H), 2.58 to 2.75 (m, 1H), 7 .45 (t, J = 7.8 Hz, 2H), 7.55 (tt, J = 1.5, 7.4 Hz, 1H), 7.67 (q, J = 0.8 Hz, 1H), 8. 17-8.21 (m, 2H), 8.23 (s, 1H), 8.28 (d, J = 2.1 Hz, 1H), 8.33 (d, J = 2.1 Hz, 1H).

Data for cis isomer (IIb-85): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.46 to 1.61 (m, 4H), 1.66 to 1.75 (m, 4H), 1.81 To 2.04 (m, 2H), 2.14 to 2.19 (m, 1H), 2.39 to 2.48 (m, 4H), 2.68 to 2.77 (m, 1H), 7 .45 (t, J = 7.7 Hz, 2H), 7.54 (tt, J = 1.5, 7.4 Hz, 1H), 7.66 (q, J = 0.8 Hz, 1H), 8. 16 to 8.23 (m, 3H), 8.35 (d, J = 2.1 Hz, 1H), 8.38 (d, J = 2.1 Hz, 1H).

2- (1- (phenylsulfonyl) -5- (1,4-dioxaspiro [4.5] dec-7-en-8-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl) Thiazole (IIa-86)

Bromide (III-j) (1.41 g, 3.35 mmol), boronic acid (VIb) in EtOH (10 mL), toluene (10 mL) and 1.0 M Na ₂ CO ₃ solution (5.0 mL, 5.0 mmol). −36) (1.00 g, 3.76 mmol), LiCl (400 mg, 9.48 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (140 mg, 0.20 mmol) were prepared according to General Procedure A for the Suzuki reaction. And reacted under reflux for 3 hours. The crude product (2.35 g; dark brown oil) was purified by SGC using AcOEt: CH ₂ Cl ₂ : hexane = 1: 1: 2 (v / v / v) to give (IIa-86) (1.24 g, 2.77 mmol, 83%) was obtained as a light brown foam. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.97 (t, J = 6.5 Hz, 2H), 2.50 to 2.54 (m, 2H), 2.72 to 2.78 (m, 2H) 4.06 (s, 4H), 6.04 to 6.08 (m, 1H), 7.35 (d, J = 3.3 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.62 (tt, J = 1.5, 7.4 Hz, 1H), 7.91 (d.J = 3.3 Hz, 1H), 8.24-8.28 (m, 3H), 8.58 (d, J = 2.2 Hz, 1H), 8.59 (d, J = 2.2 Hz, 1H).

2- (1- (phenylsulfonyl) -5- (1,4-dioxaspiro [4.5] decan-8-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole (IIb- 87)

Using the general procedure for hydrogenation of 7-azaindole over 2 days using 20% Pd (OH ₂ ) / C (Degussa form, 100 mg) in MeOH (13 mL) and CH ₂ Cl ₂ (7 mL) Compound (IIa-86) (1.24 g, 2.30 mmol) was hydrogenated. The reaction mixture was then filtered through celite, washed with ethanol (100 mL) and concentrated to give an oil (1.18 g). The oil was purified by SGC using AcOEt: CH ₂ Cl ₂ : hexane = 1: 1: 2 (v / v / v) to foam (IIb-87) (803 mg, 1.79 mmol, 60%). Obtained as a product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.69 to 1.80 (m, 2H), 1.83 to 1.97 (m, 6H), 2.72 to 2.81 (m, 1H), 4 0.02 (s, 4H), 7.35 (d, J = 3.3 Hz, 1H), 7.53 (t, J = 7.7 Hz, 2H), 7.62 (tt, J = 1.5, 7.5 Hz, 1H), 7.91 (d.J = 3.3 Hz, 1H), 8.24-8.29 (m, 3H), 8.42 (d, J = 2.1 Hz, 1H), 8.48 (d, J = 2.1 Hz, 1H).

2- (1- (phenylsulfonyl) -5- (1,4-dioxaspiro [4.5] decan-8-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole (IIb- 87)-Alternative method of preparation

Iodide (IXb-23) (100 mg, 0.19 mmol) and 2- (tributylstannyl) thiazole (107 mg, 0.29 mmol), tri-O-tolylphosphine (7 mg, 0.02 mmol), dichlorobis (acetonitrile) palladium (II) (3 mg, 0.01 mmol) and toluene (3 mL) were reacted in a sealed reaction vessel at 120 ° C. (oil bath) for 5 hours using General Procedure B for Stille reaction. The reaction mixture was filtered, concentrated and LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. 50mm) to give (IIb-87) (42.2 mg, 46%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.57 to 1.64 (m, 2H), 1.68 to 1.76 (m, 2H), 1.86 to 1.91 (m, 4H), 2 .70-2.78 (m, 1H), 3.99 (s, 4H), 7.33 (d, J = 3.3 Hz, 1H), 7.48-7.52 (m, 2H), 7 .60 (tt, J = 1.5, 7.4 Hz, 1H), 7.89 (d.J = 3.3 Hz, 1H), 8.23 (s, 1H), 8.24-8.26 ( m, 2H), 8.39 (d, J = 2.1 Hz, 1H), 8.45 (d, J = 2.1 Hz, 1H).

4- (1- (phenylsulfonyl) -3- (thiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexanone (IIb-88)

To a stirred solution of (IIb-87) (803 mg, 1.79 mmol) in THF (25 mL) was added 6.0 M aqueous HCl (10 mL, 60 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The solution was then slowly added to saturated aqueous NaHCO ₃ (250 mL) and the mixture was extracted with AcOEt (3 × 200 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated to give (IIb-88) (740 mg, 1.83 mmol, quantitative) as a clear oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.00 to 2.14 (m, 2H), 2.24 to 2.33 (m, 2H), 2.52 to 2.60 (m, 4H), 3 .23 (tt, J 3.4, 12.2 Hz, 1H), 7.36 (d, J = 3.3 Hz, 1H), 7.54 (t, J = 7.8 Hz, 2H), 7.63 (Tt, J = 1.5, 7.4 Hz, 1H), 7.91 (d.J = 3.3 Hz, 1H), 8.25-8.30 (m, 3H), 8.45 (d, J = 2.2 Hz, 1H), 8.53 (d, J = 2.2 Hz, 1H).

4-((1r, 4r) -4- (1- (phenylsulfonyl) -3- (thiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (IIb -89) and 4-((1s, 4s) -4- (1- (phenylsulfonyl) -3- (thiazol-2-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl ) Morpholine (IIb-90)

Ketone (IIb-88) (148 mg, 0.34 mmol), morpholine (88 mg, 1.01 mmol), acetic acid (41 mg, 0.68 mmol) in 1,2-dichloroethane (3 mL) and NaBH (OAc) ₃ (143 mg). 0.68 mmol) was reacted according to general procedure B for reductive amination. The crude product (151 mg, oil) was purified by SGC using AcOEt: CH ₂ Cl ₂ : MeOH (50: 50: 0 to 45:45:10, v / v / v gradient elution) as eluent. . The first to elute was the cis isomer (IIb-90) (86 mg, 0.17 mmol, 50%). Further elution gave the trans isomer (IIb-89) (44 mg, 0.09 mmol, 26%) as a solid.

Data of trans isomer (IIb-89): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.37-1.50 (m, 2H), 1.54-1.68 (m, 2H), 1.99 To 2.14 (m, 4H), 2.36 (tt, J = 3.4, 11.4 Hz, 1H), 2.59 to 2.72 (m, 5H), 3.76 (t, J = 4.6 Hz, 2H), 7.34 (d, J = 3.3 Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.61 (tt, J = 1.5, 7 .5 Hz, 1 H), 7.90 (d J = 3.3 Hz, 1 H), 8.23 to 8.29 (m, 3 H), 8.39 (d, J = 2.1 Hz, 1 H), 8. 44 (d, J = 2.1 Hz, 1H).

Data for cis isomer (IIb-90): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.52-1.71 (m, 4H), 1.96-2.09 (m, 4H), 2.26 ˜2.32 (m, 1H), 2.43 to 2.57 (m, 4H), 2.81 to 2.90 (m, 1H), 3.77 (t, J = 4.6 Hz, 2H) 7.36 (d, J = 3.3 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.63 (tt, J = 1.5, 7.4 Hz, 1H), 7.92 (d.J = 3.3 Hz, 1H), 8.25-8.30 (m, 3H), 8.46 (d, J = 2.1 Hz, 1H), 8.48 (d, J = 2.1 Hz, 1 H).

2-methyl-4- (5-((1r, 4r) -4- (4-methylpiperazin-1-yl) cyclohexyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine- 3-yl) thiazole (IIb-91) and 2-methyl-4- (5-((1s, 4s) -4- (4-methylpiperazin-1-yl) cyclohexyl) -1- (phenylsulfonyl) -1H -Pyrrolo [2,3-b] pyridin-3-yl) thiazole (IIb-92)

Ketone (IIb-73) (0.69 g, 1.53 mmol), 1-methyl-piperazine (1.70 mL, 15.32 mmol) in anhydrous methanol (15 mL), 1.25 M HCl in MeOH (4.90 mL, 6.13 mmol) NaBH ₃ CN (0.19 g, 3.06 mmol) added in one portion was reacted overnight according to general procedure A for reductive amination. The crude product was purified by SGC using CH ₂ Cl ₂ : MeOH (98: 2 to 85:15, v / v gradient) as eluent. The first to elute was the cis isomer (IIb-92) (0.178 g, 22%) as a white foam. Further elution provided the trans isomer (IIb-91) (0.192 g, 23%) as a white foam.

Data of trans isomer (IIb-91): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.41-1.65 (m, 4H), 2.03 (d, J = 12 Hz, 2H), 2.36 (S, 3H), 2.45 to 2.69 (m, 7H), 2.72 to 2.80 (m, 3H), 2.70 to 2.79 (br s, 3H), 2.81 ( s, 3H), 7.30 (s, 1H), 7.45-7.50 (m, 2H), 7.54-7.59 (m, 1H), 8.11 (d, J = 2. 1 Hz, 2H), 8.15 (s, 3H), 8.22 to 8.20 (m, 2H), 8.34 (d, J = 2.1 Hz, 1H).

Data for cis isomer (IIb-92): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.63-1.75 (m, 4H), 1.94-2.06 (m, 4H), 2.55 (S, 3H), 2.52 to 2.59 (m, 1H), 2.80 (s, 3H), 2.63 to 2.98 (m, 9H), 7.36 (s, 1H), 7.46 to 7.51 (m, 2H), 7.55 to 7.60 (m, 1H), 8.15 (s, 1H), 8.18 to 8.22 (m, 3H), 8. 42 (d, J = 2.0 Hz, 1H).

4- (3- (2- (1- (Methylpiperidin-4-yl) thiazol-4-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexanone ( IIb-93)

7N aqueous HCl (1.88 mL, 13.13 mmol) was added in one portion to a solution of ketal (IIb-23) (0.76 g, 1.31 mmol) in THF (10 mL) at room temperature and the mixture was stirred at room temperature for 5 hours. . The reaction mixture was then slowly poured into a saturated aqueous solution of NaHCO ₃ (100 mL) over 20 minutes. It was extracted with EtOAc (4 × 50 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated to give (IIb-93) as a white foam (0.57 g, 81%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.92 to 2.07 (m, 4H), 2.11 to 2.30 (m, 6H), 2.35 (s, 3H), 2.48 to 2 .60 (m, 4H), 2.95 to 3.03 (m, 2H), 3.07 (tt, J = 3.8, 11.6 Hz, 1H), 3.20 (tt, J = 3. 8, 11.6 Hz, 1H), 7.34 (s, 1H), 7.46 to 7.52 (m, 2H), 7.55 to 7.60 (m, 1H), 8.13 (s, 1H), 8.20-8.25 (m, 3H), 8.40 (d, J = 2.0 Hz, 1H).

4-((1r, 4r) -4- (3- (2- (1-methylpiperidin-4-yl) thiazol-4-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] Pyridin-5-yl) cyclohexyl) morpholine (IIb-94) and 4-((1s, 4s) -4- (3- (2- (1-methylpiperidin-4-yl) thiazol-4-yl)- 1- (Phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (IIb-95)

To ketone (IIb-93) (200 mg, 0.37 mmol), morpholine (326 mg, 3.75 mmol), 1.25 M HCl in MeOH (0.60 mL, 0.75 mmol) in anhydrous methanol (10 mL) at once. Added NaBH ₃ CN (47 mg, 0.75 mmol) was reacted overnight according to general procedure A for reductive amination. The crude product was purified by PTLC using CH ₂ Cl ₂ : MeOH = 9: 1 (v / v) as the eluent to give an impure and unidentified cis isomer (IIb-95) (45 mg, 20 %), And the trans isomer (IIb-94) (48 mg, 21%) was obtained.

Data of trans isomer (IIb-94): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.36-1.48 (dq, J = 2.1, 12.5 Hz, 2H), 1.48-1. 60 (dq, J = 2.1, 12.5 Hz, 2H), 1.95 to 2.25 (m, 12H), 2.35 (s, 3H), 2.58 to 2.63 (m, 4H) ), 2.96-3.15 (m, 3H), 3.74 (t, J = 4.6 Hz, 4H), 7.33 (s, 1H), 7.44-7.50 (m, 2H) ), 7.52 to 7.58 (m, 1H), 8.12 (m, 2H), 8.18 to 8.22 (m, 2H), 8.33 (d, J = 2.0 Hz, 1H) ).

4- (5-((1r, 4r) -4- (4-methylpiperazin-1-yl) cyclohexyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) 2- (1-Methylpiperidin-4-yl) thiazole (IIb-96) and 4- (5-((1s, 4s) -4- (4-methylpiperazin-1-yl) cyclohexyl) -1- ( Phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -2- (1-methylpiperidin-4-yl) thiazole (IIb-97)

To ketone (IIb-93) (200 mg, 0.37 mmol), 1-methylpiperazine (374 mg, 3.74 mmol) in anhydrous methanol (10 mL) and 1.25 M HCl in MeOH (0.60 mL, 0.75 mmol). NaBH ₃ CN (47 mg, 0.75 mmol) added in one portion was reacted overnight according to general procedure A for reductive amination. The crude product was purified by PTLC using CHCl ₃ : MeOH: NH ₄ OH = 90: 9: 1 (v / v / v) as the eluent to contain the impure and uncharacterized cis isomer (IIb -97) (29 mg, 12%) and the trans isomer (IIb-96) (44 mg, 19%) were obtained.

Data of trans isomer (IIb-96): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.39 to 1.61 (m, 2H), 1.94 to 2.10 (m, 8H), 2.17 ˜2.26 (m, 4H), 2.32 (s, 3H), 2.36 (s, 3H), 2.40 to 2.50 (tt, J = 3.3, 11.2 Hz, 1H) 2.51 to 2.66 (m, 4H), 2.66 to 2.77 (m, 2H), 3.00 to 3.06 (m, 2H), 3.05 to 3.12 (tt, J = 3.8, 11.5 Hz, 4H), 7.33 (s, 1H), 7.44-7.49 (m, 2H), 7.52-7.59 (m, 1H), 8. 11 (d, J = 2.2 Hz, 1H), 8.12 (s, 1H), 8.19 to 8.22 (m, 2H), 8.33 (d, J = 2.0 Hz, 1H). MS calcd _{C 33 H 42 N 6 O 2} S 2 M = 618, measured value ^{(M + H) + = 619.4} .

2- (1-Methylpiperidin-4-yl) -4- (1- (phenylsulfonyl) -5-((1r, 4r) -4- (pyrrolidin-1-yl) cyclohexyl) -1H-pyrrolo [2, 3-b] pyridin-3-yl) thiazole (IIb-98) and 2- (1-methylpiperidin-4-yl) -4- (1- (phenylsulfonyl) -5-((1s, 4s) -4 -(Pyrrolidin-1-yl) cyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole (IIb-99)

To ketone (IIb-93) (172 mg, 0.32 mmol), pyrrolidine (229 mg, 3.23 mmol) in anhydrous methanol (10 mL) and 1.25 M HCl in MeOH (0.52 mL, 0.65 mmol) at once. Added NaBH ₃ CN (40.5 mg, 0.64 mmol) was reacted overnight according to general procedure A for reductive amination. The crude product was purified by PTLC using CH ₂ Cl ₂ : MeOH: NH ₄ OH = 800: 199: 1 (v / v / v) as eluent to give the cis isomer (IIb-99) (37 mg , 19%) and the trans isomer (IIb-98) (59 mg, 31%).

Data of trans isomer (IIb-98): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.48 to 1.61 (m, 4H), 1.81 to 1.92 (m, 4H), 1.93 To 2.01 (m, 4H), 2.10 to 2.22 (m, 7H), 2.34 (s, 3H), 2.64 to 2.81 (m, 4H), 2.93 to 3 .01 (m, 3H), 3.0-3.10 (tt, J = 3.7, 11.5 Hz, 1H), 7.34 (s, 1H), 7.44-7.50 (m, 2H), 7.54-7.59 (m, 1H), 8.12 (s, 1H), 8.13 (s, 1H), 8.19-8.23 (m, 2H), 8.34 (D, J = 2.0 Hz, 1H).

Data for cis isomer (IIb-99): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.62-1.73 (m, 4H), 1.88-2.05 (m, 10H), 2.11. -2.25 (m, 6H), 2.34 (s, 3H), 2.67-2.84 (m, 4H), 2.93-3.10 (m, 3H), 7.45-7 .50 (m, 3H), 7.53 to 7.59 (m, 1H), 8.17 (m, 1H), 8.20 to 8.23 (m, 2H), 8.27 (d, J = 2.0 Hz, 1H), 8.37 (d, J = 2.0 Hz, 1H).

4- (4- (3- (2- (1-Methylpiperidin-4-yl) thiazol-4-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl ) Cyclohex-3-enyl) -1,4-oxazepane (IIa-101) and 4- (4- (3- (2- (1-methylpiperidin-4-yl) thiazol-4-yl) -1H- Pyrrolo [2,3-b] pyridin-5-yl) cyclohex-3-enyl) -1,4-oxazepane (I-101)

Bromide (III-h) (1.00 g, 1.93 mmol), boronic acid (VIb) in EtOH (30 mL), toluene (30 mL) and 1.0 M Na ₂ CO ₃ solution (19.3 mL, 19.3 mmol) -101) (0.71 g, 2.32 mmol), LiCl (0.25 g, 5.80 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (0.13 g, 0.19 mmol) were added to the general reaction for the Suzuki reaction. Reacted under reflux using general procedure A for 72 hours. The crude product was purified by SGC using AcOEt: hexane (50:50 to 100: 0, v / v gradient) followed by AcOEt: MeOH (100: 0 to 90:10, v / v gradient). (IIa-101) (0.14 g, 12%) and (I-101) (0.23 g, 25%) were obtained as a pale red solid.

(IIa-101) data: ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.81 to 2.00 (m, 5H), 2.04 to 2.28 (m, 5H), 2.32 (s, 3H), 2.36 to 2.44 (m, 1H), 2.53 to 2.59 (m, 2H), 2.76 to 2.87 (m, 5H), 2.90 to 3.07 ( m, 4H), 3.73 (t, J = 4.6 Hz, 2H), 3.80 (t, J = 6.1 Hz, 2H), 6.04 to 6.09 (m, 1H), 7. 33 (s, 1H), 7.42-7.46 (m, 2H), 7.51-7.57 (m, 1H), 8.12 (s, 1H), 8.17-8.20 ( m, 2H), 8.23 (d, J = 2.1 Hz, 1H), 8.48 (d, J = 2.1 Hz, 1H).

(I-101) data: ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.68 to 1.76 (m, 1H), 1.89 to 2.03 (m, 4H), 2.08 to 2. 16 (m, 2H), 2.17 to 2.31 (m, 4H), 2.35 (s, 3H), 2.40 to 2.49 (m, 1H), 2.63 to 2.73 ( m, 2H), 2.86 to 2.90 (m, 4H), 2.94 to 3.03 (m, 3H), 3.03 to 3.12 (m, 1H), 3.78 (t, J = 4.7 Hz, 2H), 3.85 (t, J = 6.0 Hz, 2H), 6.08 to 6.11 (m, 1H), 7.24 (s, 1H), 7.82 ( d, J = 2.4 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 9.82 (brs, NH, 1H).

4-((1r, 4r) -4- (3- (2- (1-methylpiperidin-4-yl) thiazol-4-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] Pyridin-5-yl) cyclohexyl) -1,4-oxazepane (IIb-102) and 4-((1s, 4s) -4- (3- (2- (1-methylpiperidin-4-yl) thiazole-) 4-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepane (IIb-103)

Using the general procedure for hydrogenation of 7-azaindole using 20% Pd (OH ₂ ) / C (Degussa form, 30 mg) in MeOH (5 mL) and AcOEt (5 mL) over 20 h, compound (IIa -101) (100 mg, 1.87 mmol) was hydrogenated. The reaction mixture was then filtered through celite, washed with CH ₂ Cl ₂ : MeOH = 1: 1 and concentrated to give a white foam. The foam was purified by PTLC SGC using CHCl ₃ : MeOH: NH ₄ OH = 90: 9: 1 (v / v / v) to give the cis isomer (IIb-103) (10 mg, 10%; High R _f ) was obtained as a white foam and trans isomer (IIb-102) (20 mg, 20%; low R _f ) was obtained as a white foam.

Data of trans isomer (IIb-102): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.40 to 1.65 (m, 4H), 1.85 to 2.07 (m, 8H), 2.10 -2.25 (m, 4H), 2.35 (s, 3H), 2.60-2.70 (m, 2H), 2.81-2.90 (m, 4H), 2.97-3 .10 (m, 3H), 3.74 (t, J = 4.6 Hz, 2H), 3.81 (t, J = 5.9 Hz, 2H), 7.33 (s, 1H), 7.45 -7.50 (m, 2H), 7.54-7.59 (m, 1H), 8.13 (s, 2H), 8.20-8.23 (m, 2H), 8.34 (d , J = 2.1 Hz, 1H).

Data for cis isomer (IIb-102): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.59-1.75 (m, 4H), 1.86-2.14 (m, 10H), 2.14 ˜2.25 (m, 4H), 2.36 (s, 3H), 2.83 to 2.92 (m, 4H), 2.97 to 3.12 (m, 3H), 3.76 (t , J = 4.7 Hz, 2H), 3.80 (t, J = 5.8 Hz, 2H), 7.39 (s, 1H), 7.46 to 7.51 (m, 2H), 7.54. ˜7.59 (m, 1H), 8.13 (s, 1H), 8.21 to 8.24 (m, 2H), 8.27 (s, 1H), 8.41 (d, J = 1) .9Hz, 1H).

2- (1-Methylpyrrolidin-2-yl) -4- (1- (phenylsulfonyl) -5- (1,4-dioxaspiro [4.5] dec-7-en-8-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole (IIa-104)

Bromide (III-q) (1.10 g, 2.18 mmol) in EtOH (21.8 ml), toluene (21.8 ml) and 1.0 M Na ₂ CO ₃ solution (5.5 mL, 5.5 mmol), Boronic acid (VIb-36) (0.70 g, 2.62 mmol), LiCl (0.28 g, 6.55 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (0.15 g, 0.22 mmol) were combined with the Suzuki reaction. Reacted under reflux using general procedure A for 72 hours. The crude product was purified by SGC using AcOEt: hexane (0: 100 to 100: 0, v / v gradient) to give (IIa-104) (0.91 g, 74%) as a gray solid. Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.83 to 2.03 (m, 3H), 1.96 (t, J = 6.3 Hz, 2H), 2. 39 to 2.45 (m, 1H), 2.45 to 2.48 (m, 1H), 2.47 (s, 3H), 2.48 to 2.52 (m, 2H), 2.68 to 2.76 (m, 2H), 3.25 to 3.33 (tt, J = 1.6, 7.2 Hz, 1H), 3.78 to 3.82 (dd, J = 6.3, 8. 8 Hz, 1 H), 4.04 (s, 4 H), 5.98 to 6.02 (tt, J = 1.5, 3.9 Hz, 1 H), 7.39 (s, 1 H), 7.44 to 7.49 (m, 2H), 7.54 to 7.58 (m, 1H), 8.16 (s, 1H), 8.19 to 8.23 (m, 2H), 8.25 (d, J = 2.1 z, 1H), 8.53 (d, J = 2.1Hz, 1H).

2- (1-Methylpyrrolidin-2-yl) -4- (1- (phenylsulfonyl) -5- (1,4-dioxaspiro [4.5] decan-8-yl) -1H-pyrrolo [2,3 -B] pyridin-3-yl) thiazole (IIb-105)

Using the general procedure for hydrogenation of 7-azaindole using 20% Pd (OH ₂ ) / C (Degussa form, 0.35 g) in MeOH (50 mL) -EtOAc (50 mL) over 20 h (IIa-104) (0.91 g, 1.62 mmol) was hydrogenated. The reaction mixture was then filtered through celite, washed with CH ₂ Cl ₂ : MeOH = 1: 1 and concentrated to give crude (IIb-105) as a white solid (0.81 g, 89%), which was There was no need for further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.66 to 1.78 (m, 3H), 1.81 to 1.95 (m, 5H), 1.97 to 2.15 (m, 2H), 2 .45 to 2.59 (m, 2H), 2.71 (s, 3H), 2.70 to 2.77 (m, 1H), 3.05 (t, J = 7.3 Hz, 1H), 3 .13 (t, J = 7.3 Hz, 1H), 3.26-3.38 (m, 1H), 3.99 (s, 4H), 7.42 (s, 1H), 7.45-7 .51 (m, 2H), 7.54 to 7.59 (m, 1H), 8.12 (s, 1H), 8.17 (s, 1H), 8.21 to 8.25 (m, 2H) ), 8.37 (d, J = 2.1 Hz, 1H).

4- (3- (2- (1-Methylpyrrolidin-2-yl) thiazol-4-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexanone ( IIb-106)

7N aqueous HCl (1.02 mL, 7.17 mmol) was added in one portion to a solution of ketal (IIb-105) (0.81 g, 1.43 mmol) in THF (4 mL) at room temperature and the mixture was stirred at room temperature overnight. The reaction mixture was then slowly poured into a saturated aqueous solution of NaHCO ₃ (100 mL) over 30 minutes. It was extracted with EtOAc (4 × 50 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated to give (IIb-106) (0.74 g, 99%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.66 to 1.76 (m, 1H), 1.83 to 2.05 (m, 5H), 2.20 to 2.29 (m, 2H), 2 .44 to 2.48 (m, 1H), 2.46 (s, 3H), 2.51 to 2.57 (m, 4H), 3.19 (tt, J = 3.2, 12.4 Hz, 1H), 3.27 (tt, J = 1.6, 7.1 Hz, 1H), 3.77 to 3.82 (dd, J = 6.0, 8.6 Hz, 1H), 7.38 (s) , 1H), 7.44-7.50 (m, 2H), 7.56-7.59 (m, 1H), 8.15 (s, 1H), 8.18-8.22 (m, 3H) ), 8.39 (d, J = 2.1 Hz, 1H).

4-((1r, 4r) -4- (3- (2- (1-methylpyrrolidin-2-yl) thiazol-4-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] Pyridin-5-yl) cyclohexyl) morpholine (IIb-107) and 4-((1s, 4s) -4- (3- (2- (1-methylpyrrolidin-2-yl) thiazol-4-yl)- 1- (Phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (IIb-108)

To ketone (IIb-106) (170 mg, 0.33 mmol), morpholine (284 mg, 3.26 mmol) in anhydrous methanol (10 mL) and 1.25 M HCl in MeOH (0.52 mL, 0.65 mmol) at once. Added NaBH ₃ CN (41 mg, 0.65 mmol) was reacted overnight according to general procedure A for reductive amination. The crude product was purified by PTLC using CH ₂ Cl ₂ : MeOH = 95: 5 (v / v) as eluent to give the cis isomer (IIb-108) (37 mg, 19%) as a white foam And trans isomer (IIb-107) (53 mg, 27%) was obtained as a white foam.

Data of trans isomer (IIb-107): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.37-1.49 (dq, J = 2.2, 12.5 Hz, 2H), 1.50-1. 62 (dq, J = 2.2, 12.9 Hz, 2H), 1.83 to 2.13 (m, 8H), 2.31 to 2.50 (m, 2H), 2.46 (s, 3H) ), 2.59-2.67 (m, 5H), 3.27 (tt, J = 1.9, 7.2 Hz, 1H), 3.76 (t, J = 4.5 Hz, 4H), 3 .78 (dd, J = 6.1, 8.7 Hz, 1H), 7.38 (s, 1H), 7.44-7.50 (m, 2H), 7.53-7.58 (m, 1H), 8.09 (d, J = 2.0 Hz, 1H), 8.16 (s, 1H), 8.20 to 8.23 (m, 2H), 8.34 (d, J = 2. 0Hz, H).

Data for cis isomer (IIb-108): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.49-1.65 (m, 4H), 1.83 to 2.05 (m, 8H), 2.37 -2.52 (m, 6H), 2.47 (s, 3H), 2.81 (tt, J = 3.8, 10.5 Hz, 1H), 3.28 (tt, J = 1.7, 7.9 Hz, 1H), 3.75 (t, J = 4.2 Hz, 4H), 3.78-3.82 (dd, J = 6.1, 8.9 Hz, 1H), 7.39 (s) , 1H), 7.45-7.50 (m, 2H), 7.54-7.59 (m, 1H), 8.15 (m, 1H), 8.18 (s, 1H), 8. 20 to 8.23 (m, 2H), 8.40 (d, J = 2.0 Hz, 1H).

4- (5-((1r, 4r) -4- (4-methylpiperazin-1-yl) cyclohexyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) 2- (1-methylpyrrolidin-2-yl) thiazole (IIb-109) and 4- (5-((1s, 4s) -4- (4-methylpiperazin-1-yl) cyclohexyl) -1- ( Phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -2- (1-methylpyrrolidin-2-yl) thiazole (IIb-110)

To ketone (IIb-106) (163 mg, 0.31 mmol), 1-methylpiperazine (313 mg, 3.13 mmol) in anhydrous methanol (10 mL) and 1.25 M HCl in MeOH (0.50 mL, 0.63 mmol). NaBH ₃ CN (39 mg, 0.63 mmol) added in one portion was reacted overnight according to general procedure A for reductive amination. The crude product was purified by PTLC using CH ₂ Cl ₂ : MeOH = 90: 10 (v / v) as eluent to give the cis isomer (IIb-110) (23 mg, 12%) and the trans isomer. (IIb-109) (31 mg, 16%) was obtained.

Data of trans isomer (IIb-109): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.42 (m, 4H), 1.83 to 2.06 (m, 6H), 2.06 to 2.13 (D, J = 11.5 Hz, 2H), 2.35 (s, 3H), 2.46 (s, 3H), 2.54 to 2.70 (m, 6H), 2.71 to 2.82 (Br s, 5H), 3.27 (t, J = 7.9 Hz, 1H), 3.78-3.83 (dd, J = 6.2, 8.8 Hz, 1H), 7.38 (s , 1H), 7.45-7.50 (m, 2H), 7.54-7.59 (m, 1H), 8.09 (d, J = 2.0 Hz, 1H), 8.16 (s) , 1H), 8.19 to 8.23 (m, 2H), 8.33 (d, J = 2.0 Hz, 1H).

Data of cis isomer (IIb-110): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.51 to 1.67 (m, 4H), 1.85 to 1.92 (m, 1H), 1.93 -2.05 (m, 7H), 2.28-2.34 (m, 2H), 2.32 (s, 3H), 2.47 (s, 3H), 2.40-2.65 (br m, 8H), 2.82 (tt, J = 3.8, 10.2 Hz, 1H), 3.25 (t, J = 7.9 Hz, 1H), 3.78-3.83 (dd, J = 6.1, 8.7 Hz, 1H), 7.40 (s, 1H), 7.46-7.50 (m, 2H), 7.55-7.59 (m, 1H), 8.15. (S, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.20-8.23 (m, 2H), 8.41 (d, J = 2.0 Hz, 1H).

2- (1-methylpyrrolidin-2-yl) -4- (1- (phenylsulfonyl) -5-((1r, 4r) -4- (pyrrolidin-1-yl) cyclohexyl) -1H-pyrrolo [2, 3-b] Pyridin-3-yl) thiazole (IIb-111) and 2- (1-methylpyrrolidin-2-yl) -4- (1- (phenylsulfonyl) -5-((1s, 4s) -4 -(Pyrrolidin-1-yl) cyclohexyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole (IIb-112)

To ketone (IIb-106) (140 mg, 0.27 mmol), pyrrolidine (191 mg, 2.69 mmol) in anhydrous methanol (10 mL) and 1.25 M HCl in MeOH (0.43 mL, 0.54 mmol) at once. Added NaBH ₃ CN (34 mg, 0.54 mmol) was reacted overnight according to general procedure A for reductive amination. The crude product was purified by PTLC using CH ₂ Cl ₂ : MeOH = 90: 10 (v / v) as eluent to give the cis isomer (IIb-112) (10 mg, 6%) and the trans isomer. (IIb-111) (23 mg, 15%) was obtained.

Data of trans isomer (IIb-111): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.50 to 1.62 (dq, J = 2.6, 12.4 Hz, 2H), 1.75 to 2. 07 (m, 15H), 2.18 to 2.27 (m, 2H), 2.38 to 2.47 (m, 1H), 2.46 (s, 3H), 2.57 to 2.68 ( m, 1H), 2.73 (tt, J = 3.1, 12.4 Hz, 1H), 2.95 (br s, 2H), 3.27 (tt, J = 1.8, 8.0 Hz, 1H), 3.79-3.84 (dd, J = 6.1, 8.8 Hz, 1H), 7.38 (s, 1H), 7.45-7.50 (m, 2H), 7. 54-7.59 (m, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.15 (s, 1H), 8.19-8.22 (m, 2H), 8. 32 (D, J = 2.0 Hz, 1H).

Data for cis isomer (IIb-112): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.72-1.80 (m, 4H), 1.81-1.89 (m, 4H), 1.92 To 2.00 (m, 2H), 2.08 to 2.18 (br m, 5H), 2.34 to 2.64 (m, 10H), 2.44 (s, 3H), 2.74 to 2.84 (m, 1H), 3.27 (tt, J = 1.5, 7.2 Hz, 1H), 3.78 (dd, J = 6.4 Hz, 8.2 Hz, 1H), 7.44 To 7.52 (m, 3H), 7.53 to 7.58 (m, 1H), 8.20 to 8.23 ((m, 2H), 8.27 (, s, 1H), 8.33 (D, J = 1.8 Hz, 1H), 8.68 (brs, 1H).

4-((1r, 4r) -4- (3- (2- (1-methylpyrrolidin-2-yl) thiazol-4-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] Pyridin-5-yl) cyclohexyl) -1,4-oxazepane (IIb-113) and 4-((1s, 4s) -4- (3- (2- (1-methylpyrrolidin-2-yl) thiazole-) 4-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepane (IIb-114)

Ketone (IIb-106) (200 mg, 0.38 mmol), homomorpholine hydrochloride (310 mg, 2.25 mmol) in 1.25 M HCl in MeOH (0.43 mL, 0.54 mmol) and anhydrous methanol (5 mL) and General Procedure A for Reductive Amination of NaBH ₃ CN (34 mg, 0.54 mmol) added to N-ethyldiisopropylamine (0.27 mL, 1.53 mmol) as a MeOH (2 mL) solution at −20 ° C. And reacted overnight. The crude product was purified by PTLC using CH ₂ Cl ₂ : MeOH = 90: 10 (v / v) as eluent to give the cis isomer (IIb-114) (32 mg, 14%) as a colorless thick oil. And trans isomer (IIb-113) (46 mg, 20%) was obtained.

Data of trans isomer (IIb-113): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.49-1.67 (m, 4H), 1.83-2.15 (m, 10H), 2.39 ˜2.48 (m, 1H), 2.47 (s, 3H), 2.61 to 2.67 (m, 1H), 2.84 to 2.94 (m, 1H), 2.95 to 3 0.06 (m, 4H), 3.28 (t, J = 7.4 Hz, 1H), 3.78-3.85 (m, 5H), 7.40 (s, 1H), 7.46-7 .50 (m, 2H), 7.54-7.59 (m, 1H), 8.11 (d, J = 2.0 Hz, 1H), 8.16 (s, 1H), 8.19-8 .23 (m, 2H), 8.33 (d, J = 2.0 Hz, 1H).

Data for cis isomer (IIb-114): ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.71-1.81 (m, 4H), 1.85-2.04 (m, 8H), 2.08 To 2.20 (m, 2H), 2.37 to 2.45 (m, 1H), 2.47 (s, 3H), 2.90 to 2.98 (m, 1H), 2.98 to 3 .13 (m, 5H), 3.27 (tt, J = 1.7, 7.8 Hz, 1H), 3.77 to 3.86 (m, 5H), 7.44 to 7.51 (m, 2H), 7.54-7.59 (m, 1H), 8.17 (s, 1H), 8.20-8.24 (m, 2H), 8.25n (d, J = 1.9 Hz, 1H), 8.41 (d, J = 2.1 Hz, 1H).

4- (1- (phenylsulfonyl) -5- (1,4-dioxaspiro [4.5] decan-8-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole (IIb- 115)

Iodide (IXb-23) (100 mg, 0.19 mmol) and 4- (tributylstannyl) thiazole (107 mg, 0.29 mmol), tri-O-tolylphosphine (7 mg, 0.02 mmol), dichlorobis (acetonitrile) palladium (II) (3 mg, 0.01 mmol) and toluene (3 mL) were reacted in a sealed reaction vessel at 120 ° C. (oil bath) for 1 hour using General Procedure B for Stille reaction. The reaction mixture was filtered, concentrated and LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. 50 mm) to give (IIb-115) (22.2 mg, 24%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.68-1.90 (m, 8H), 2.69-2.76 (m, 1H), 3.99 (m, 4H), 7.46-7 .50 (m, 2H), 7.52 (d, J = 1.9 Hz, 1H), 7.57 (tt, J = 7.4, 1.5 Hz, 1H), 8.17 (s, 1H) 8.22 to 8.25 (m, 3H), 8.38 (d, J = 1.9 Hz, 1H), 8.93 (d, J = 1.9 Hz, 1H).

4-((1r, 4r) -4- (3- (4-methylthiazol-2-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepan (IIb-117)

Iodide (IXb-75a) (150 mg, 0.27 mmol), 4-methyl-2- (tributylstannyl) thiazole (154 mg, 0.40 mmol), tri-O-tolylphosphine (10 mg, 0.03 mmol), dichlorobis (Acetonitrile) palladium (II) (4 mg, 0.02 mmol) and toluene (3 mL) were reacted in a sealed reaction vessel at 120 ° C. (oil bath) for 5 hours using General Procedure B for Stille reaction. I let you. The reaction mixture was filtered, concentrated and LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent. 50 mm) and then purified by PTLC on amino silica plates (Chromatorex NH, Fuji Silysia) to give (IIb-117) (38.8 mg, 26.9%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.41 to 1.63 (m, 4H), 1.84 to 1.90 (m, 2H), 1.96 to 2.03 (m, 4H), 2 .53 (d, J = 1.0 Hz, 3H), 2.58 to 2.69 (m, 2H), 2.79 to 2.84 (m, 4H), 3.71 to 3.74 (m, 2H), 3.81 (t, J = 6.1 Hz, 2H), 6.87 (d, J = 1.0 Hz, 1H), 7.47 to 7.52 (m, 2H), 7.58 ( tt, J = 7.5, 1.5 Hz, 1H), 8.21 to 8.24 (m, 3H), 8.31 to 8.36 (m, 2H).

4-((1r, 4r) -4- (1- (tert-butyldimethylsilyl) -3- (thiazol-5-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepan (IIb-118)

Crude stannane (XXVIII-75) (250 mg, ca. 0.30 mmol), 5-bromothiazole (88 mg, 0.53 mmol), tri-O-tolylphosphine (21 mg, 0.07 mmol), dichlorobis (acetonitrile) palladium (II) (9 mg, 0.04 mmol) and toluene (2 mL) were reacted at 85 ° C. for 18 hours using a modified general procedure B for Stille reaction. The crude product was purified by PTLC using LCMS with CHCl ₃ : MeOH: NH ₄ OH = 93: 6: 1 (v / v / v) to give (Ib-118) and (XXVIIb-75). A mixture (15.10 mg) was obtained, which was used directly for further steps without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) spectrum: δ 0.65 (s, 6H), 0.96 (s, 9H), 1.46 to 1.67 (m, 4H), 1.91 to 2.10 (M, 6H), 2.53 to 2.77 (m, 2H), 2.85 to 2.95 (m, 4H), 3.75 to 3.80 (m, 2H), 3.82 (t , J = 6.0 Hz, 2H), 7.41 (s, 1H), 7.88 (d, J = 2.1 Hz, 1H), 8.03 (s, 1H), 8.22 (d, J = 2.1 Hz, 1H), selective resonance at 8.74 (s, 1H).

4-((1r, 4r) -4- (1- (tert-butyldimethylsilyl) -3- (2-methoxythiazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-5-yl ) Cyclohexyl) morpholine (IIb-120)

Bromide (IXb-29) (312.00 mg, 0.65 mmol), tri-O-tolylphosphine (39.69 mg, 0.13 mmol), PdCl ₂ (MeCN) ₂ (16.91 mg) in toluene (3.0 mL). , 0.07 mmol) and 2-methoxy-4- (tributylstannyl) thiazole (289.88 mg, 0.72 mmol) were reacted for 18 hours using General Procedure B for Stille reaction. LCMS (column LUNA 10μ C18 (2) 00G-4253-V0 250 × 50 mm) using water-acetonitrile (0.1% AcOH) (gradient; flow rate 80 mL / min) as eluent, then CH ₂ as eluent The crude product was purified by SGC using Cl ₂ : EtOAc: MeOH (50: 50: 0 to 45:45:10; v / v / v gradient elution) to give (IIb-120). (289.00 mg, 60.00% purity, 0.34 mmol, 52%).

4-((1r, 4r) -4- (3- (5-methylthiazol-2-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepan (IIb-121)

Iodide (IXb-75a) (101 mg, 0.18 mmol), 5-methyl-2- (tributylstannyl) thiazole (104 mg, 0.27 mmol), tri-O-tolylphosphine (7 mg, 0.02 mmol), dichlorobis (Acetonitrile) palladium (II) (3 mg, 0.01 mmol) and toluene (3 mL) were added at 120 ° C. (oil bath) in a sealed reaction vessel at 5.5 ° C. using general procedure B for Stille reaction. Reacted for hours. The reaction mixture was filtered, concentrated and purified by PTLC on amino silica plates (Chromatorex NH, Fuji Silysia) to give (IIb-121) (18.3 mg, 19%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.38 to 1.61 (m, 4H), 1.83 to 1.90 (m, 2H), 1.95 to 2.01 (m, 4H), 2 .53 (s, 3H), 2.57 to 2.68 (m, 2H), 2.78 to 2.84 (m, 4H), 3.71 to 3.75 (m, 2H), 3.81 (T, J = 5.9 Hz, 2H), 7.49 to 7.52 (m, 3H), 7.56 to 7.61 (m, 1H), 8.13 (s, 1H), 8.21 ~ 8.24 (m, 2H) and 8.33-8.37 (m, 2H).

4-((1r, 4r) -4- (1- (phenylsulfonyl) -3- (2- (pyrrolidin-1-yl) thiazol-4-yl) -1H-pyrrolo [2,3-b] pyridine- 5-yl) cyclohexyl) -1,4-oxazepane (IIb-122)

Iodide (IXb-75a) (100 mg, 0.18 mmol), 2- (pyrrolidin-1-yl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Thiazole (55 mg, 0.19 mmol), LiCl (22 mg, 0.53 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (6 mg, 0.008 mmol) and 1.0 M Na ₂ CO ₃ A mixture of solution (0.44 mL, 0.44 mmol) in EtOH (2 mL) and toluene (2 mL) was reacted for 4.5 h according to General Procedure B for Suzuki reaction. The product was purified by PTLC on amino silica plates (Fuji Silysia, Chromatorex NH) to give (IIb-122) (30.1 mg, 28%). ¹ 1 H NMR (400 MHz, CDCl ₃ ) Δ 1.39 to 1.61 (m, 4H), 1.66 to 1.79 (m, 2H), 1.88 (t, J = 5.4 Hz, 2H), 1.95 to 2.03 (M, 4H), 2.06 to 2.11 (m, 4H), 2.54 to 2.68 (m, 2H), 2.79 to 2.86 (m, 2H), 3.51 to 3 .56 (m, 4H), 3.72 to 3.75 (m, 2H), 3.81 (t, J = 5.9 Hz, 2H), 6.63 (s, 1H), 7.43 to 7 .48 (m, 2H), 7.54 (tt, J = 7.4 and 1.6 Hz, 1H), 8.03 (s, 1H), 8.10 (d, J = 2.1 Hz, 1H) 8.18-8.22 (m, 2H), 8.30 (d, J = 2.1 Hz, 1H).

4-((1r, 4r) -4- (3- (4,5-dimethylthiazol-2-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) (Cyclohexyl) -1,4-oxazepane (IIb-123)

Iodide (IXb-75a) (150 mg, 0.26 mmol), 4,5-dimethyl-2- (tributylstannyl) thiazole (160 mg, 0.39 mmol), tri-O-tolylphosphine (10 mg, 0.03 mmol) , Dichlorobis (acetonitrile) palladium (II) (4 mg, 0.02 mmol) and toluene (3 mL) using a general procedure B for Stille reaction at 120 ° C. (oil bath) in a sealed reaction vessel. Reacted for hours. The reaction mixture was filtered, concentrated and purified by PTLC on aminosilica plates (Chromatorex NH, Fuji Silysia) using hexane: EtOAc = 1: 1 (v / v) as eluent to give (IIb-123 ) Was obtained (70.3 mg, 48%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.38 to 1.63 (m, 4H), 1.83 to 1.91 (m, 2H), 1.95 to 2.03 (m, 4H), 2 .40 (s, 3H), 2.41 (s, 3H), 2.57 to 2.69 (m, 2H), 2.79 to 2.85 (m, 4H), 3.71 to 3.75 (M, 2H), 3.81 (t, J = 6.0 Hz, 2H), 7.46 to 7.51 (m, 2H), 7.58 (tt, J = 7.4, 1.6 Hz, 1H), 8.14 (s, 1H), 8.20 to 8.23 (m, 2H), 8.29 (d, J = 2.1 Hz, 1H), 8.34 (d, J = 2. 1 Hz, 1 H).

4-((1r, 4r) -4- (3- (2-methoxythiazol-4-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepan (IIb-124)

Iodide (IXb-75a) (150 mg, 0.26 mmol), 2-methoxy-4- (tributylstannyl) thiazole (161 mg, 0.39 mmol), tri-O-tolylphosphine (10 mg, 0.03 mmol), dichlorobis (Acetonitrile) palladium (II) (4 mg, 0.02 mmol) and toluene (3 mL) were reacted in a sealed reaction vessel at 120 ° C. (oil bath) for 2 hours using General Procedure B for Stille reaction. I let you. The reaction mixture was filtered, concentrated and purified by PTLC on aminosilica plates (Chromatorex NH, Fuji Silysia) using hexane: EtOAc = 1: 1 (v / v) as eluent to give (IIb-124 ) Was obtained (94.4 mg, 64%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.38 to 1.61 (m, 4H), 1.82 (m, 2H), 1.95 to 2.02 (m, 4H), 2.55 to 2 .67 (m, 2H), 2.78 to 2.84 (m, 4H), 3.70 to 3.75 (m, 2H), 3.80 (t, J = 6.0 Hz, 2H), 4 .17 (s, 3H), 6.83 (s, 1H), 7.44-7.50 (m, 2H), 7.56 (tt, J = 7.4, 1.6 Hz, 1H), 8 .06 (d, J = 2.0 Hz, 1H), 8.09 (s, 1H), 8.19 to 8.23 (m, 2H), 8.32 (d, J = 2.0 Hz, 1H) .

4-((1r, 4r) -4- (3- (2-ethoxythiazol-4-yl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepan (IIb-125)

Iodide (IXb-75a) (150 mg, 0.26 mmol), 2-ethoxy-4- (tributylstannyl) thiazole (166 mg, 0.39 mmol), tri-O-tolylphosphine (10 mg, 0.03 mmol), dichlorobis (Acetonitrile) palladium (II) (4 mg, 0.02 mmol) and toluene (3 mL) were added at 120 ° C. (oil bath) in a sealed reaction vessel at 4.3 ° C. using general procedure B for Stille reaction. Reacted for hours. The reaction mixture was filtered, concentrated and purified by PTLC on aminosilica plates (Chromatorex NH, Fuji Silysia) using hexane: EtOAc = 1: 1 (v / v) as eluent to give (IIb-125 ) Was obtained (82.3 mg, 54%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.39 to 1.60 (m, 4H), 1.49 (t, J = 7.1 Hz, 3H), 1.83 to 1.90 (m, 2H) 1.95 to 2.02 (m, 4H), 2.55 to 2.67 (m, 2H), 2.78 to 2.84 (m, 4H), 3.70 to 3.75 (m, 2H), 3.80 (t, J = 6.0 Hz, 2H), 4.12 (q, J = 7.1, 14.2 Hz, 2H), 6.81 (s, 1H), 7.45. 7.50 (m, 2H), 7.56 (tt, J = 7.4, 1.6 Hz, 1H), 8.05 (d, J = 2.1 Hz, 1H), 8.08 (s, 1H) ), 8.19-8.23 (m, 2H), 8.32 (d, J = 2.1 Hz, 1H).

4- (1-Benzenesulfonyl-5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) -thiazole-2-carboxylic acid ethyl ester (III-a)

Compound (XXIII-a) (6.08 g, 14.0 mmol), n-Bu ₄ NHSO ₄ (100 mg, catalytic amount), PhSO ₂ Cl (2.50 mL, 19.5 mmol) in CH ₂ Cl ₂ (75 mL) And 50% aqueous NaOH (2 mL) were reacted at room temperature according to the general procedure for protection for 1.5 hours (XXIII). The crude product was recrystallized from CH ₂ Cl ₂ / hexane to give pure (III-a) (2.33 g) as a yellow solid. Further product was obtained from the mother liquor by SGC using hexane: CH ₂ Cl ₂ : EtOAc (2: 1: 1, v / v / v) as eluent. Total yield of (III-a) (4.40 g, 8.94 mmol, 57%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.51 (t, J = 7.2 Hz, 3H), 4.55 (q, J = 7.1 Hz, 2H), 7.53 (t, J = 7. 8 Hz, 2H), 7.63 (t, J = 7.5 Hz, 1H), 7.74 (s, 1H), 8.24 (d, J = 7.8 Hz, 1H), 8.30 (s, 1H), 8.54 (d, J = 2.1 Hz, 1H), 8.56 (d, J = 2.1 Hz, 1H).

(4- (5-Bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazol-2-yl) (piperidin-1-yl) methanone (III-c)

Compound (XXIII-c) (770 mg, 1.97 mmol), n-Bu ₄ NHSO ₄ (100 mg, 0.294 mmol), PhSO ₂ Cl (0.40 mL, 554 mg, 3.12 mmol) in CH ₂ Cl ₂ (10 mL). ) And 50% aqueous NaOH (1 mL) were reacted according to the general procedure for protection at room temperature for 1.5 hours (XXIII). The crude brown oil (738 mg) was purified by SGC using AcOEt: hexane 1: 4 (v / v) to give (III-c) (385 mg, 0.72 mmol, 37%) as a solid. . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.71 to 1.88 (m, 6H), 3.76 to 3.84 (m, 2H), 4.31 to 4.39 (m, 2H), 7 .53 (t, J 7.7 Hz, 2H), 7.63 (tt, J 1.2, 7.5 Hz, 1H), 7.68 (s, 1H), 8.16 (s, 1H), 8 .21 to 8.26 (m, 2H), 8.52 (d, J = 2.2 Hz, 1H), 8.58 (d, J = 2.2 Hz, 1H).

4- [4- (1-Benzenesulfonyl-5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) -thiazol-2-yl] -piperidine-1-carboxylic acid tert-butyl ester ( III-f)

Compound (XXIII-f) (1.24 g, 2.68 mmol), n-Bu ₄ NHSO ₄ (120 mg, 0.35 mmol), PhSO ₂ Cl (0.50 mL, 690 mg, 3 in CH ₂ Cl ₂ (15 mL) .90 mmol) and 50% aqueous NaOH (0.5 mL) were reacted at room temperature overnight according to the general procedure for protection (XXIII). Crude (III-f) (840 mg) was obtained as a pale yellow solid. Upon standing overnight, a precipitate appeared in the aqueous extract, which was filtered to give additional (III-f) (710 mg) as a white powder. The two solids were combined to give (III-f) as an off-white solid (1.55 g, 2.57 mmol, 96%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.51 (s, 9H), 1.79 (dd, J = 4.4, 12.6 Hz, 2 × 1H), 1.84 (dd, J = 4.4) 12.6 Hz, 2 × 1H), 2.19 (br d, J = 12.6 Hz, 2H), 2.95 (br t, J = 12.3 Hz, 2H), 3.25 (tt, J = 3.8) , 11.6 Hz, 1H), 4.26 (brs, 2H), 7.37 (s, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.62 (t, J = 7.5 Hz, 1 H), 8.17 (s, 1 H), 8.22 (d, J = 7.8 Hz, 1 H), 8.52 (d, J = 2.4 Hz, 1 H), 8.54 ( d, J = 2.4 Hz, 1H).

4- (5-Bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -2- (piperidin-4-yl) thiazole (III-g)

To a stirred solution of (III-f) (5.80 g, 9.61 mmol) in CH ₂ Cl ₂ (40 mL) was added CF ₃ COOH (5 mL). The reaction was stirred at room temperature for 2 hours. The reaction mixture was then slowly poured into saturated NaHCO3 solution (300 mL) and the mixture was stirred for 20 minutes. It was extracted with EtOAc (3 x 300 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated to give the crude product, which was triturated with MeOH (20 mL). The solid was filtered to give (III-g) (4.80 g, 99%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.95 to 2.06 (dq, J = 3.8 and 12.5 Hz, 2H), 2.20 to 2.29 (dd, J = 2.4 and 13 .3 Hz, 2H), 2.48 to 2.57 (dt, J = 2.4 and 11.8 Hz, 2H), 2.99 to 3.08 (tt, J = 3.8 and 11.4 Hz, 1H) ) 3.90-3.97 (m, 2H), 7.35 (s, 1H), 7.47-7.51 (m, 2H), 7.55-7.60 (m, 1H), 8.12 (s, 1H), 8.18 to 5.21 (m, 2H), 8.48 (d, J = 2.2 Hz, 1H), 8.49 (d, J = 2.2 Hz, 1H) ).

1-benzenesulfonyl-5-bromo-3- [2- (1-methyl-piperidin-4-yl) -thiazol-4-yl] -1H pyrrolo [2,3-b] pyridine (III-h)

To a stirred solution of (III-g) (4.80 g, 9.53 mmol) in THF (40 mL) was added a 40% aqueous solution of formaldehyde (10 mL). Acetic acid (0.03 mL, 0.48 mmol) was added. The mixture was stirred at room temperature for 30 minutes. NaBH (OAc) ₃ (4.04 g, 19.07 mmol) was added in one portion. The reaction was stirred at room temperature overnight. Saturated NaHCO ₃ solution (400 mL) was slowly added to the reaction mixture over 20 minutes until gas evolution ceased. It was extracted with CH ₂ Cl ₂ (3 × 400 mL). The combined organic extracts were dried (MgSO _4), and concentrated to give (III-h) (3.81g, 77%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.90 to 2.02 (m, 2H), 2.11 to 2.18 (m, 4H), 2.33 (s, 3H), 2.95 to 3 .10 (m, 3H), 7.27 (s, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 8.06 (S, 1H), 8.12 (d, J = 7.7 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H) .

1-benzenesulfonyl-5-bromo-3- [2- (1-methyl-piperidin-4-yl) -thiazol-4-yl] -1H pyrrolo [2,3-b] pyridine (III-h) − ( Alternative preparation without isolating III-g)

To a stirred solution of (III-f) (1.55 g, 2.57 mmol) in CH ₂ Cl ₂ (10 mL) was added CF ₃ COOH (5 mL). After 1 hour, the solvent was concentrated to dryness and THF (5 mL) was added. To the resulting suspension of (III-g) TFA salt was added formaldehyde (40% aqueous solution, 1 mL, excess), acetic acid (3 drops, catalyst) and NaBH (OAc) ₃ (800 mg, 3.77 mmol). . The reaction mixture was stirred overnight and then quenched by the addition of 1.0 N aqueous HCl (10 mL, 10 mmol). The mixture was then neutralized with 1.0 N aqueous NaOH (ca. 10 mL, 10 mmol) and extracted with AcOEt (3 × 50 mL). The organic extracts were combined, dried (MgSO _4), and concentrated to give the (III-h) (840mg, 1.62mmol, 63%) as a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.85 to 2.00 (m, 2H), 2.07 to 2.23 (m, 4H), 2.33 (s, 3H), 2.93 to 3 .07 (m, 3H), 7.27 (s, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 8.06 (S, 1H), 8.12 (d, J = 7.7 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H) .

4- (5-Bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -N, N-diethylthiazol-2-amine (III-i)

Crude compound (XXIII-i) (2.97 g, ca. 7.19 mmol), n-Bu ₄ NHSO ₄ (100 mg, 0.3 mmol), PhSO ₂ Cl (1.20 mL, 9) in CH ₂ Cl ₂ (25 mL). .38 mmol) and 50% aqueous NaOH (2.0 mL) were reacted at room temperature for 2 h (XXIII) following the general procedure of protection. The crude product (3.87 g) was triturated with MeOH (50 mL) to give (III-i) (2.14 g, estimated purity 85%) as a light brown powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.31 (t, J = 7.1 Hz, 6H), 3.57 (q, J = 7.1 Hz, 4H), 6.64 (s, 1H), 7 .50 (t, J = 7.7 Hz, 2H), 7.60 (tt, J = 1.5, 7.5 Hz, 1H), 8.11 (s, 1H), 8.20 (d, J = 7.8 Hz, 2H), 8.48 (d, J = 2.2 Hz, 1H), 8.51 (d, J = 2.2 Hz, 1H).

2- (5-Bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole (III-j)

Bromide (IV-a) in toluene (30 mL) (4.35 g, 9.39 mmol; prepared as disclosed in WO 2004/078756), 2- (tributylstannyl) thiazole (3.71 g, 9.92 mmol), tri -O-Tolylphosphine (355 mg, 1.17 mmol) and bis (acetonitrile) dichloropalladium (II) (150 mg, 0.58 mmol) were reacted for 6 hours using the general procedure A for Stille reaction (bath). Temperature 110 ° C.). The crude product (dark brown oil, 8.89 g) was purified by silica gel chromatography using CH ₂ Cl ₂ as the eluent to give (III-j) as a pale yellow foam (1 .72 g, 4.09 mmol, 44%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37 (d, J = 3.3 Hz, 1H), 7.55 (t, J = 7.7 Hz, 2H), 7.65 (tt, J = 1. 5, 7.5 Hz, 1 H), 7.91 (d, J = 3.3 Hz, 1 H), 8.22 to 8.29 (m, 3 H), 8.55 (d, J = 2.2 Hz, 1 H) ), 8.83 (d, J = 2.2 Hz, 1H).

4- (5-Bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -2-methylthiazole (III-k)

Compound (XXIII-k) (2.63 g, 8.94 mmol), n-Bu ₄ NHSO ₄ (250 mg, 0.74 mmol), PhSO ₂ Cl (2.21 g, 12.52 mmol) in CH ₂ Cl ₂ (50 mL). ) And 50% aqueous NaOH (1.0 mL) were allowed to react according to the general procedure of protection for 2 hours (XXIII) at room temperature. The solution was then poured into saturated aqueous NaHCO ₃ (100 mL) and extracted with AcOEt (2 × 100 mL). The combined organic portions were dried over MgSO ₄ and concentrated to give a brown solid. The solid was triturated with MeOH (50 mL) to give (III-k) as a white powder (3.28 g, 7.54 mmol, 84%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.72 (s, 3H), 7.22 (s, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.53 (tt, J = 1.5, 7.5 Hz, 1 H), 8.08 (s, 1 H), 8.10 to 8.13 (m, 2 H), 8.42 (d, J = 2.2 Hz, 1 H), 8 .45 (d, J = 2.2 Hz, 1H).

2- (5-Bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -4- (trifluoromethyl) thiazole (III-l)

To a stirred solution of (XIII-a) (5.65 g, 14.26 mmol) in THF (50 mL) was added 3-bromo-1,1,1-trifluoro-propan-2-one (3.01 g, 15.74 mmol). Was added dropwise over 10 minutes. The reaction mixture was then stirred at room temperature for 18 hours, added to saturated aqueous NaHCO ₃ (100 mL) and extracted with AcOEt (2 × 100 mL). The combined organic portions were dried (MgSO ₄ ) and concentrated to give crude hydroxythiazoline (10.16 g). Desorption to thiazole was performed by dissolving in THF (100 mL), adding trifluoroacetic anhydride (5 mL), and stirring at room temperature for 18 hours. The mixture was then poured into saturated aqueous NaHCO ₃ (250 mL) and extracted with AcOEt (2 × 250 mL). The combined organic portions were dried over MgSO ₄ and concentrated to give an oil (8.34 g) which was purified by SGC using AcOEt: hexane = 1: 4 (v / v) as eluent to contain impurities. The product was obtained (5.11 g, estimated purity 85%). The product was further purified by trituration with Et ₂ O (100 mL) to give (III-l) as a white powder (1.71 g, 3.50 mmol, 25%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (t, J = 7.8 Hz, 2H), 7.67 (tt, J = 1.5, 7.5 Hz, 1H), 7.78 (q, J = 0.8 Hz, 1H), 8.24-8.29 (m, 2H), 8.33 (s, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.76 ( d, J = 2.3 Hz, 1H).

tert-Butyl 4- (2- (5-bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazol-4-yl) piperidine-1-carboxylate (III -M)

To a solution of (XIII-a) (3.60 g, 9.08 mmol) in THF (50 mL) was added tert-butyl 4- (2-bromoacetyl) piperidine-1-carboxylate (2) (3.03 g, 9.90 mmol). Bioorg. Med. Chem. Lett. 2004, 14, 3419, ibid. 2005, 15, 2129)) was added and the reaction mixture was stirred at room temperature for 11 days. Saturated aqueous NaHCO ₃ (100 mL) was then added and the mixture was extracted with AcOEt (2 × 150 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated to give (III-m) (6.02 g, ˜85% purity, 8.48 mmol, 93%) as a yellow solid, which was further Used without purification.

2- (5-Bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -4- (1-methylpiperidin-4-yl) thiazole (III-n)

To a stirred solution of (III-m) (6.02 g, ca. 85% purity, 8.48 mmol) in CH ₂ Cl ₂ (100 mL) was added CF ₃ COOH (50 mL) and the reaction mixture was stirred at room temperature for 2 h. The solution was then concentrated and then azeotroped with toluene (2 × 100 mL) to give an off-white solid (7.96 g). The solid was dissolved in THF (100 mL) and aqueous formaldehyde (37%, 3.0 mL). After stirring at room temperature for 10 minutes, NaBH (OAc) ₃ (2.70 g, 12.72 mmol) was added and the solution was stirred for 18 hours. The mixture was then diluted with AcOEt (300 mL) and washed with saturated aqueous NaHCO ₃ (3 × 100 mL). The organic layer was dried (MgSO ₄ ) and concentrated to give a solid (4.39 g). The solid was triturated with Et ₂ O (50 mL), the off-white powder was discarded, the filtrate was evaporated to give (III-n) (3.04 g, purity about 92%, 5.40 mmol, 64%) Was obtained as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.83 to 1.95 (m, 2H), 2.08 to 2.20 (m, 4H), 2.37 (s, 3H), 2.78 to 2 .88 (m, 1H), 2.98 to 3.08 (m, 2H), 6.91 (s, 1H), 7.54 (t, J = 7.8 Hz, 2H), 7.64 (tt , J = 1.5, 7.5 Hz, 1H), 8.21 to 8.27 (m, 3H), 8.54 (d, J = 2.1 Hz, 1H), 8.75 (d, J = 2.1 Hz, 1H).

4- [4tert-Butyl 2- (4- (5-Bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) thiazol-2-yl) pyrrolidine-1-carboxy Rate (III-o)

Compound (XXIII-o) (2.44 g, 5.44 mmol), n-Bu ₄ NHSO ₄ (185 mg, 0.54 mmol), PhSO ₂ Cl (0.97 mL, 7.61 mmol) in CH ₂ Cl ₂ (20 mL). ) And 50% aqueous NaOH (2.17 mL) were reacted at room temperature overnight according to the general procedure for protection (XXIII). The solution was then poured into saturated aqueous NaHCO ₃ (100 mL) and extracted with CH ₂ Cl ₂ (3 × 100 mL). The combined organic portions were dried (MgSO ₄ ) and concentrated to give a brown solid. The solid was purified by SCG using EtOAc: hexane (0: 100 to 100: 0, v / v gradient elution) as eluent to give the product (III-o) as a yellow solid (2. 65 g, 83%). The compound exists as a rotamer. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.35 (s, 6H), 1.50 (s, 3H), 1.93 to 2.04 (m, 2H), 2.24 to 2.47 (m , 2H), 3.45 to 3.70 (m, 2H), 5.21 (d, J = 6 Hz, 0.6H), 5.26 to 5.33 (br s, 0.4H), 7. 36 (br s, 1H), 7.50 (t, J = 7.7 Hz, 2H), 7.60 (t, J = 7.2 Hz, 1H), 8.10 to 8.24 (m, 3H) 8.49 (s, 1H), 8.52 (s, 0.6H), 8.53 (s, 0.4H).

4- (5-Bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -2- (pyrrolidin-2-yl) thiazole (III-p)

To a stirred solution of (III-o) (2.65 g, 4.50 mmol) in CH ₂ Cl ₂ (20 mL) was added CF ₃ COOH (3.46 mL). The reaction was stirred at room temperature for 30 minutes. The reaction mixture was then slowly poured into a saturated aqueous solution of NaHCO ₃ (300 mL) and the mixture was stirred for 20 minutes. The mixture was extracted with EtOAc (3 × 300 mL). The combined organic extracts were dried (MgSO _4), and concentrated to give the crude product (III-p) (1.65g, 75%). ¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD several drops) δ 1.88 to 2.00 (m, 2H), 2.04 to 2.13 (m, 2H), 2.34 to 2.49 (m , 1H), 3.12 to 3.26 (m, 2H), 4.68 to 4.72 (dd, J = 6.0, 8.5 Hz, 1H), 7.37 (s, 1H), 7 .45 to 7.50 (m, 2H), 7.55 to 7.61 (m, 1H), 8.15 (s, 1H), 8.15 to 5.18 (m, 2H), 8.45 (D, J = 2.1 Hz, 1H), 8.46 (d, J = 2.1 Hz, 1H).

4- (5-Bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -2- (1-methylpyrrolidin-2-yl) thiazole (III-q)

To a stirred solution of (III-p) (1.65 g, 3.37 mmol) in THF (50 mL) was added 40% aqueous formaldehyde solution (5 mL) and AcOH (0.02 mL, 0.33 mmol). The mixture was stirred at room temperature for 30 minutes. NaBH (AcO) ₃ (2.14 g, 10.11 mmol) was added in one portion at room temperature. The reaction was stirred at room temperature overnight. Until gas evolution ceased, saturated NaHCO ₃ solution (150 mL) was added slowly over 20 minutes to the reaction. The mixture was extracted with EtOAc (3 × 150 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated. The crude product was purified by SGC using CH ₂ Cl ₂ : hexane (0: 100 to 100: 0, v / v gradient elution) to give (III-q) (1.11 g, 65%). It was. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 1.82~2.04 (m, 3H), 2.37~2.51 (m, 2H), 2.46 (s, 3H), 3.24~3 .33 (tt, J = 1.5, 7.4 Hz, 1H), 3.78 to 3.82 (dd, J = 6.0, 8.5 Hz, 1H), 7.38 (s, 1H), 7.47 to 7.52 (m, 2H), 7.57 to 7.62 (m, 1H), 8.17 (s, 1H), 8.19 to 8.21 (m, 2H), 8. 49 (d, J = 2.1 Hz, 1H), 8.51 (d, J = 2.1 Hz, 1H).

Synthesis of boronic acid ester (VIb-54)

4- (1,4-Dioxa-spiro [4.5] dec-8-yl) -morpholine (1)

A mixture of 1,4-dioxaspiro [4.5] decan-8-one (10.0 g, 64.0 mmol), morpholine (20 mL) and AcOH (1.0 mL) was stirred for 2.5 hours. Then sodium cyanoborohydride (8.05 g, 128.0 mmol) was added in one portion, followed by more morpholine (15 mL). An exothermic reaction occurred and the mixture was cooled in an ice bath for 2 minutes. The mixture was then stirred at room temperature for 16 hours. Ethanol (120 mL) and water (28 mL) were added to the resulting thick slurry and the white solid was filtered and washed with ethanol (twice) and the filtrate was concentrated. Then ethyl acetate was added, the precipitate was filtered off, washed with ethyl acetate and the filtrate was concentrated. The remaining oil was purified by Kugelrohr distillation to give 1 (9.03 g, 62%; boiling point 140 ° C./0.05 mmHg) as a clear oil that solidified on standing.

4- (1,4-Dioxa-spiro [4.5] dec-8-yl) -morpholine (1) -alternative method

Sodium triacetoxyborohydride (382 g, 1.8 mol), 1,4-dioxaspiro [4.5] decan-8-one (200.0 g, 1.28 mol), morpholine (111.4 g, 1.28 mol) And ice AcOH (73.2 mL, 1.28 mol) was added in one portion to a mixture of 1,2-dichloroethane (4 L). A slight exothermic reaction occurred, with the temperature rising by 12 ° C. The mixture was then stirred at room temperature overnight. The reaction was quenched by adding 10% aqueous NaOH (1.8 L) over 20 minutes. The organic layer was separated, washed with brine (1 L), dried over MgSO ₄ and concentrated to give 1 (237.66 g) as a white solid. The aqueous layer was extracted with AcOEt (4 × 300 mL). The combined extracts were washed with brine (1 L), dried over MgSO ₄ and concentrated to give a further 1 (44 g) as an off-white solid. Total yield of 1 (281.66 g, 97%). ¹ H NMR was identical to previously obtained data.

4-morpholin-4-yl-cyclohexanone (VII-a)

To a solution of 1 (4.50 g, 19.8 mmol) in THF (100 mL) was added 7N aqueous HCl (40 mL). The reaction mixture was stirred for 17 hours and quenched by pouring into saturated aqueous NaHCO ₃ (475 mL). The mixture was extracted with ethyl acetate (1 ×) then CH ₂ Cl ₂ (3 ×) and the combined organic extracts were dried (MgSO ₄ ) and concentrated. The resulting oil was purified by Kugelrohr distillation to give (VII-a) (3.17 g, 87%) as a clear oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.80 to 1.94 (m, 2H), 1.80 to 2.10 (m, 2H), 2.30 (m, 1H), 2.45-2 .65 (m, 8H), 3.74 (t, J = 4.7 Hz, 4H).

Trifluoromethanesulfonic acid 4-morpholin-4-yl-cyclohex-1-enyl ester (VIIIa-36)

Using the general procedure for the synthesis of enol triflate, ketone (VII-a) (5.30 g, 28.9 mmol) in dry THF (100 mL), 1M solution of LiHMDS in THF (34.7 mL, 34.7 mmol). ) And N-phenylbis (trifluoromethanesulfinimide) (11.37 g, 31.8 mmol) were used to prepare the triflate (VIIIa-54). The crude product was purified by SGC using ethyl acetate: hexane: Et ₃ N = 39: 60: 1 (v / v / v) (gradient elution starting at 19: 80: 1) as eluent to give triflate. The rate (VIIIa-54) (7.66 g, 84%) was obtained as an orange oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.61-1.72 (m, 1H), 2.07 (m, 1H), 2.20 (m, 1H), 2.30-2.48 (m , 3H), 2.50 to 2.65 (m, 5H), 3.72 (t, J = 4.7 Hz, 4H), 5.72 (m, 1H).

4- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxazolidin-2-yl) -cyclohex-3-enyl] -morpholine (VIb-54)

Compounds were prepared using the general procedure for the synthesis of boronic acid pinacol esters. Triflate (VIIIa-54) (8.00 g, 25.4 mmol), bis (pinacolatodiboron) (9.66 g, 38.1 mmol), potassium acetate (7.47 g, 76.1 mmol) in DMF (110 mL) ) And dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (1.04 g, 1.27 mmol) were stirred at 85 ° C. for 17 hours. The crude product was purified by SGC using ethyl acetate: hexane = 1: 1 (v / v) (gradient elution) as eluent to give (VIb-54) (4.95 g, 67%) as pale orange As a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.26 (s, 12H), 1.95 to 2.10 (m, 2H), 2.05 to 2.20 (m, 2H), 2.80 to 2 .40 (m, 2H), 2.43 to 2.65 (m, 5H), 3.74 (t, J = 4.7 Hz, 4H), 6.51 (m, 1H).

Synthesis of boronic acid ester (VIb-101)

4- (1,4-Dioxaspiro [4.5] decan-8-yl) -1,4-oxazepane (3)

Et ₃ N (96.9 mL, 0.695 mol) was added to 1,2-dichloroethane (1.81 L) of homomorpholine hydrochloride (79.76 g, 0.579 mol) and ketone 1 (90.5 g, 0.579 mol). Added to the stirred suspension all at once. Glacial acetic acid (34.8 mL, 0.607 mol) was then added in one portion, followed by solid NaBH (OAc) ₃ (154 g, 0.727 mol) in one portion as well. This increased the temperature of the reaction mixture by 5 ° C. After 2 hours 45 minutes, the reaction was quenched by the addition of 10% aqueous NaOH (800 mL). The mixture was stirred for 10 minutes. The organic layer was separated, washed with brine (100 mL), dried (MgSO ₄ ) and concentrated to give an oil (142.36 g) with some suspended solid, which was filtered off (3.00 g ). The aqueous portion of the reaction mixture was combined with the brine wash and extracted with AcOEt (4 × 500 mL). The combined extracts were washed with brine (100 mL), dried (MgSO ₄ ) and concentrated to give more oil (16.82 g). The two oily products were combined and vacuum distilled to give 3 (101.07 g, 72%) as a colorless liquid, boiling point 122 ° C./8.9 10 ⁻³ mbar. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 1.48~1.64 (m, 4H), 1.70~1.88 (m, 6H), 2.50~2.63 (m, 1H), 2 71-2.81 (m, 4H), 3.66-3.72 (m, 2H), 3.78 (t, J = 6.0 Hz, 2H), 3.93 (s, 4H).

4- (1,4-Oxazepan-4-yl) cyclohexanone (VII-b)

To a cooled (<15 ° C.) solution of 3 (10.31 g, 42.75 mmol) in THF (216 mL) was added 7N aqueous HCl (86 mL, 0.602 mol) over 5 min. The cooling bath was then removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then basified to pH 8 by dropwise addition of 50% aqueous NaOH (48 g, 0.602 mol) over 30 minutes while maintaining the internal temperature at 10-13 ° C. using an external cooling bath (0 ° C.). Turned into. Hexane (50 mL) was added and the organic layer was separated, dried over MgSO ₄ and concentrated to give a yellow liquid (7.21 g). The aqueous layer was extracted with AcOEt (4 × 50 mL). The extracts were combined, dried (MgSO ₄ ) and concentrated to give the crude product (1.58 g) as a second portion. Both portions of the crude product were combined and vacuum distilled to give ketone (VII-b) (7.27 g, 86%) as a colorless liquid, boiling point 98 ° C./5.3 10 ⁻³ mbar. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.73 to 1.85 (m, 2H), 1.89 (quintet, J = 5.9 Hz, 2H), 2.05 to 2.15 (m, 2H), 2.30 to 2.42 (m, 2H), 2.43 to 2.52 (m, 2H), 2.79 to 2.85 (m, 4H), 3.03 (tt, J = 10.4, 6.6 Hz, 1 H), 3.72 to 3.77 (m, 2 H), 3.82 (t, J = 6.0 Hz, 2 H).

4- (1,4-Oxazepan-4-yl) cyclohex-1-enyl trifluoromethanesulfonate (VIIIa-101)

Using the general procedure for the synthesis of enol triflate, ketone (VII-b) (6.49 g, 32.9 mmol) in dry THF (115 mL), 1M solution of LiHMDS in THF (39.5 mL, 39.5 mmol). ) And N-phenylbis (trifluoromethanesulfinimide) (12.94 g, 36.2 mmol) to prepare triflate (VIIIa-101). The crude reaction mixture was diluted with hexane: AcOEt = 4: 1 (115 mL) (v / v), washed with water (50 mL), brine (50 mL), dried (MgSO ₄ ) and concentrated. The liquid residue was distilled in vacuo to give (VIIIa-101) (6.98 g, 64%) as a colorless liquid, boiling point 114 ° C./5.7 10 ⁻³ mbar. About 85% purity by ¹ H NMR. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 1.63~1.76 (m, 1H), 1.86 ( quintet, J = 6.0Hz, 2H), 1.95~2.05 (m, 1H), 2.12 to 2.24 (m, 1H), 2.26 to 2.56 (m, 3H), 2.74 to 2.80 (m, 4H), 2.82 to 2.92 ( m, 1H), 3.68-3.74 (m, 2H), 3.79 (t, J = 6.0 Hz, 2H), 5.72 (dt, J = 5.7, 2.4 Hz, 1H) ).

4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) cyclohex-3-enyl) -1,4-oxazepane (VIb-101)

Compounds were prepared using the general procedure for the synthesis of boronic acid pinacol esters. Triflate (VIIIa-101) (6.60 g, 20.06 mmol), bis (pinacolatodiboron) (7.62 g, 30.09 mmol), AcOK (5.90 g, 60.2 mmol) in DMF (86 mL) And dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (0.82 g, 1.0 mmol) were stirred at 85 ° C. for 1 hour 45 minutes, when TLC was It showed that it did not remain. The mixture was concentrated and partitioned between AcOEt (125 mL) -water (125 mL). The organic layer is washed with water (120 mL), dried (MgSO ₄ ), concentrated and separated by chromatography on aminosilica (Chromatorex NH, Fuji Silysia) using hexane-AcOEt (gradient elution) as eluent. (VIb-101) (2.149 g, 35%) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.26 (s, 12H), 1.33 to 1.47 (m, 1H), 1.83 to 1.93 (m, 3H), 2.04 to 2 .22 (m, 2H), 2.23 to 2.38 (m, 2H), 2.75 to 2.84 (m, 5H), 3.71 (t, J = 4.7 Hz, 2H), 3 .80 (t, J = 6.0 Hz, 2H), 6.52 (m, 1H).

Synthesis of boronic ester (VIb-126)

1-methyl-4- (1,4-dioxaspiro [4.5] decan-8-yl) piperazine (4)

1-Methyl-piperazine (128.27 g, 105.90 ml, 1.28 mol) was added to 1,4-dioxaspiro [4.5] decan-8-one (200.00 g, 1.28 mol) of 1,2-dichloroethane. (2.0 L) was added to the stirred cooled (3 ° C.) solution in one portion. Glacial acetic acid (76.90 g, 73.31 ml, 1.28 mol) was then added in one portion and solid NaBH (OAc) ₃ (379.97 g, 1.79 mol) was added in portions over 20 minutes. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was quenched by adding 10% aqueous NaOH (3 × 450 mL) with stirring over 25 minutes. An exotherm of about 10 ° C. was observed. The mixture was stirred for 30 minutes. The organic layer was separated. The aqueous layer was further extracted with CH ₂ Cl ₂ (3 × 1 L). Brine (1000 mL) was added to the aqueous layer and extracted with EtOAc (2 × 1000 mL). The combined organic solution was dried (MgSO ₄ ) and concentrated to give 4 (305.00 g, 1.27 mol, 99.10% yield) as a brown / orange oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.45 to 1.68 (m, 4H), 1.72 to 1.90 (m, 4H), 1.99 (s, 3H), 2.45 (s , 2H), 2.56 to 2.67 (m, 1H), 2.87 (bs, 6H), 3.86 to 3.95 (m, 4H).

4- (4-Methylpiperazin-1-yl) cyclohexanone (VII-c)

To a cooled (0-5 ° C.) mixture of 4 (270.00 g, 1,123.39 mmol) and water (1283.00 mL) was added 7N aqueous HCl (1,283.87 ml, 8,987.08 mmol). . The cooling bath was then removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then basified to pH 9 by dropwise addition of 50% aqueous NaOH while maintaining the internal temperature below 35 ° C. in an ice bath. The mixture was extracted with EtOAc (3 × 2 L) followed by CH ₂ Cl ₂ (2 × 2 L). The extracts were dried (MgSO _4), and concentrated to give the (VII-c) (142.50g, 725.96mmol, 64.62%) bands orange white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.68 to 1.81 (m, 2H), 1.88 to 1.99 (m, 2H), 2.13 to 2.25 (m, 2H), 2 .17 (s, 3H), 2.25 to 2.43 (m, 5H), 2.43 to 2.70 (m, 5H).

4- (4-Methylpiperazin-1-yl) cyclohex-1-enyl trifluoromethanesulfonate (VIIIa-126)

Ketone (VII-c) in THF (1000 mL) (50.00 g, 254.72 mmol), 1M solution of NaHMDS in THF (382.08 ml, 1.00 M, 382.08 mmol) (this is below −40 ° C. A synthetic variant of enol triflate using N-phenylbis (trifluoromethanesulfinimide) (109.20 g, 305.67 mmol), which was added as a solution in THF (750 mL) at −78 ° C. The triflate (VIIIa-126) was prepared using the procedure. The crude reaction mixture was stirred at room temperature overnight. The reaction was quenched by adding 5% NaOH solution (1500 mL). The mixture was stirred for 5 minutes and extracted with EtOAc (3 × 2 L). The combined organic extracts were dried over MgSO ₄ and concentrated. The residue was purified by SGC on aminosilica (Chromatorex NH, Fuji Silysia) using EtOAc: hexane (0: 100 to 60:40, v / v gradient elution) as eluent to give (VIIIa-126) ( 62.00 g, 74%) was obtained as a pale yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.58 to 1.73 (m, 1H), 1.99 to 2.08 (m, 1H), 2.13 to 2.25 (m, 1H), 2 .26-2.70 (m, 12H), 2.33 (s, 3H), 5.72 (dt, J = 5.7, 2.4 Hz, 1H).

1-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) cyclohex-3-enyl) piperazine (VIb-126)

Compound (VIb-126) was prepared using the general procedure for the synthesis of boronic acid pinacol ester. Triflate (VIIIa-126) (66.0 g, 201 mmol), bis (pinacolatodiboron) (61.25 g, 241 mmol), AcOK (59.19 g, 603 mmol) and dichloro [1,1 in DMF (500 mL) '-Bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (8.28 g, 10.05 mmol) was stirred at 85 ° C. for 3 h, at which time TLC showed no starting material left. The mixture was concentrated and partitioned between EtOAc (1000 mL) -water (1000 mL). The organic layer was washed with water (1000 mL), dried (MgSO ₄ ), concentrated and aminosilica (Chromatorex) using hexane: EtOAc (100: 0 to 40:60, v / v gradient elution) as eluent. Separation by chromatography on NH, Fuji Silysia) gave (VIb-126) (32.2 g, 52%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.24 (s, 12H), 1.29 to 1.44 (m, 1H), 1.92 to 2.03 (m, 1H), 2.04 to 2 .19 (m, 2H), 2.29 (s, 3H), 2.24 to 2.39 (m, 3H), 2.39 to 2.55 (m, 4H), 2.55 to 2.83 (M, 4H), 6.47-6.55 (m, 1H).

Preparation of 4-morpholin-4-yl-cyclohexanone (VII-a)-(VIb-54) Reference Preparation of 4- (1,4-oxazepan-4-yl) cyclohexanone (VII-b)-(VIb-101) Preparation of Reference 4- (4-Methylpiperazin-1-yl) cyclohexanone (VII-c)-(VIb-126) Reference trifluoromethanesulfonic acid 4-morpholin-4-yl-cyclohex-1-enyl ester (VIIIa- 36)-Preparation of (VIb-54) Reference 4- (1,4-Oxazepan-4-yl) cyclohex-1-enyl trifluoromethanesulfonate (VIIIa-101)-Preparation of (VIb-101) Reference 4- ( 4-Methylpiperazin-1-yl) cyclohex-1-enyl trifluoromethanesulfonate (VIII a-126)-Preparation of (VIb-126) Reference 5-cyclohexyl-3-iodo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine (IXb-6)

Compound (XXVIb-6) (1.92 g, 5.89 mmol), n-Bu ₄ NHSO ₄ (0.10 g, 0.29 mmol), PhSO ₂ Cl (1.56 g, 8) in CH ₂ Cl ₂ (30 mL). .83 mmol) and 50% aqueous NaOH (0.66 mL) were reacted at room temperature for 1 h according to the general procedure for the protection of (XXIII). The crude product (3.38 g, oil) was purified by SGC using CH ₂ Cl ₂ : hexane (3: 1 v / v to pure CH ₂ Cl ₂ gradient) as eluent to give (IXb-6) Obtained as a foam (2.39 g, 5.13 mmol, 87%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.25 to 1.53 (m, 5H), 1.76 to 1.93 (m, 2H), 2.66 (tt, J = 3.0, 11. 6 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.61 (tt, J = 1.5, 7.4 Hz) , 1H), 7.84 (s, 1H), 8.20-8.25 (m, 2H), 8.32 (d, J = 2.0 Hz, 1H).

3-Iodo-1- (phenylsulfonyl) -5- (1,4-dioxaspiro [4.5] decan-8-yl) -1H-pyrrolo [2,3-b] pyridine (IXb-23)

Compound (XXVIb-23) (3.73 g, 9.72 mmol; crude), n-Bu ₄ NHSO ₄ (0.494 g, 1.46 mmol), PhSO ₂ Cl (1.92 mL) in CH ₂ Cl ₂ (60 mL). 15.0 mmol) and 50% aqueous NaOH (4.0 mL) were reacted at room temperature for 3.5 hours according to the general procedure for the protection of (XXIII). The crude product (orange oil) was stirred with cold MeOH (70 mL) for 1.5 hours. The resulting solid was filtered off to give azaindole (IXb-23) (3.96 g, 78% over 2 steps from (XXVb-23)) as a white powder.

4-((1r, 4r) -4- (3-bromo-1- (tert-butyldimethylsilyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (IXb-29)

(XXVIIb-29) (6.67g, 16.69mmol) in _CH 2 _Cl 2 (75mL) stirred solution of pyridine (1.50g, 18.96mmol) was added, followed by bromine (2.93g, 18.36mmol ) As a CH ₂ Cl ₂ (25 mL) solution dropwise over 20 minutes. After stirring at room temperature for 2 hours, the reaction was quenched by the addition of saturated aqueous Na ₂ S ₂ O ₃ (50 mL), brine (100 mL) and NaHCO ₃ (100 mL) and extracted with AcOEt (2 × 200 mL). The combined organic portions were dried over MgSO ₄ and concentrated to give the crude product (7.44 g). _{CH 2 Cl 2: MeOH = 95} : Purification by SGC using 5 (v / v), was obtained as a foam and (IXb-29) (6.19g, 12.93mmol, 78%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.50 (s, 6H), 0.83 (s, 9H), 1.26 to 1.57 (m, 5H), 1.88 to 2.03 (m , 4H), 2.19 to 2.29 (m, 1H), 2.45 to 2.57 (m, 5H), 3.61 to 3.69 (m, 4H), 7.10 (s, 1H) ), 7.50 (d, J = 1.9 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H).

4-((1r, 4r) -4- (3-bromo-1- (tert-butyldimethylsilyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepane (IXb-75)

To a stirred solution of azaindole (XXVIIb-75) (0.50 g, 1.21 mmol) in CH ₂ Cl ₂ (5 mL) and pyridine (0.12 mL, 1.45 mmol) in Br _{2 in} CH ₂ Cl ₂ (5 mL). (0.21 g, 1.33 mmol) was added over 4 minutes. After further stirring for 2.5 hours, the mixture was washed with saturated Na ₂ S ₂ O ₃ solution (2 × 15 mL) and saturated NaHCO ₃ solution (2 × 15 mL). The aqueous layer was extracted with EtOAc (4 × 25 mL). It was combined organic solutions dried (MgSO _4), filtered, and concentrated to bromide (IXb-75) (0.65g, 100%) was obtained as a viscous golden oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.60 (s, 6H), 0.93 (s, 9H), 1.43-1.65 (m, 4H), 1.90 (m, 2H), 2.00 to 2.05 (m, 4H), 2.57 to 2.66 (m, 2H), 2.84 (m, 4H), 3.75 (m, 2H), 3.82 (t, J = 6.0 Hz, 2H), 7.20 (s, 1H), 7.60 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H).

4-((1r, 4r) -4- (3-iodo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepane (IXb- 75a)

Compound (XXVIb-75) (1.55 g, 3.6 mmol), n-Bu ₄ NHSO ₄ (0.19 g, 0.55 mmol), PhSO ₂ Cl (0.72 mL, 5 mL) in CH ₂ Cl ₂ (60 mL). .6 mmol) and 50% aqueous NaOH (2.0 mL) were reacted at room temperature for 2.5 hours according to the general procedure for the protection of (XXIII). The resulting orange oil was purified by SGC on aminosilica (Chromatorex NH, Fuji Silysia) using hexane: AcOEt (75:25 to 50:50, v / v gradient elution) to give azaindole (IXb-75a) (1.06 g, 51% for 3 steps from (XXVIIb-75)) was obtained as a white powder.

5-Bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid (Xa)

A solution of sodium chlorite (9.71 g, 107.3 mmol) in water (100 mL) was added 5-bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine-3-carbaldehyde (28 0.000 g, 76.67 mmol; prepared as disclosed in WO2004101565) and sulfamic acid (10.42 g, 107.3 mmol) in water (100 mL) -1,4-dioxane (250 mL) for 1 hour. Dripped over. The temperature of the reaction mixture was maintained below 25 ° C. with an external cooling bath. The mixture was then stirred at room temperature for 1 hour and diluted with ice water (300 mL). The solid was filtered off, washed with cold water (100 mL) and diethyl ether (50 mL) and dried in vacuo overnight to give (X-a) (28.55 g, 98%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.64-7.72 (m, 2H), 7.76-7.83 (m, 1H), 8.18-8.25 (m, 2H) 8.45-8.49 (m, 2H), 8.55-8.59 (m, 1H), 13.34 (bs, 1H).

5-Bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine-3-carboxamide (XII-a)

Et ₃ N (13.5 g, 18.6 mL, 133 mmol) was added to a stirred suspension of (X-a) (28.26 g, 74.13 mmol) in CH ₂ Cl ₂ (400 mL). A clear solution formed. The solution was cooled to 0 ° C. and isobutyl chloroformate (13.16 g, 12.50 mL, 96.4 mmol) was added dropwise over 7 minutes while maintaining the temperature of the mixture at 0 ° C. Stirring was continued at 0 ° C. for 30 minutes. The mixture was then cooled to −10 ° C. and gaseous ammonia (7.31 g, 429 mmol) was rapidly introduced. The cooling bath was removed. After 6 hours, excess ammonia was evaporated and the solid was filtered off to give (XII-a) (27.94 g, 71% purity, 70% yield) as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.48 (bs, 1H), 7.60-7.70 (m, 2H), 7.72-7.80 (m, 1H), 8.08 ˜8.15 (m, 2H), 8.10 (bs, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8 79 (m, 1H).

5-Bromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridine-3-carbothioamide (XIII-a)

A mixture of (XII-a) (26.66 g; purity 71%, about 49.1 mmol) and Lawesson's reagent (42.54 g, 105.18 mmol) in THF (560 mL) was stirred at 70 ° C. under nitrogen for 1 hour and 15 minutes. . The mixture was concentrated in vacuo and the semi-solid residue was stirred with saturated aqueous NaHCO ₃ (350 mL): AcOEt (350 mL) for 10 min. The organic layer was separated and the aqueous phase was extracted with AcOEt (3 × 300 mL). The combined organic solution was washed with saturated aqueous NaHCO ₃ (100 mL), dried (MgSO ₄ ), concentrated and separated by SGC using hexane: AcOEt = 1: 3 (v / v). Fractions containing the desired product were combined and concentrated to give a solid which was washed with hexane: AcOEt = 1: 1 (v / v) (100 mL) followed by diethyl ether (50 mL) ( XIII-a) (13.91 g, purity 94%) was obtained. The combined mixed fractions and washings were purified by SGC using NH silica (Chromatorex, Fuji Silysia) and hexane: AcOEt (gradient elution) as eluent to give further (XIII-a) (2.02 g). Obtained. Total yield 15.93 g (82%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.64-7.70 (m, 2H), 7.76-7.81 (m, 1H), 8.13-8.18 (m, 2H) 8.53 (d, J = 2.3 Hz, 1H), 8.69 (s, 1H), 9.15 (d, J = 2.3 Hz, 1H), 9.57 (bs, 1H), 9 .77 (bs, 1H).

Preparation of 2-bromo-1- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) -ethanone (XXI-a)-(XXIII-a) Reference intermediate (XXIII-a) Synthesis of ~ (XXIII-b)

2-Bromo-1- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) -ethanone (XXI-a)

To a stirred solution of (XIX-a) (6.65 g, 33.8 mmol) in anhydrous CS ₂ (125 mL) was added AlCl ₃ (15.60 g, 117.0 mmol) in one portion. The reaction vessel was equipped with a reflux condenser, the temperature was brought to 50 ° C., and bromoacetyl bromide (3.00 mL, 6.95 g, 34.4 mmol) was added dropwise over 10 minutes. After stirring for an additional hour at 50 ° C., the reaction mixture was cooled to 0 ° C. and 100 mL of water (initially very carefully) was added. As soon as bubbling ceased, AcOEt (300 mL) and THF (100 mL) were added. Solid NaHCO ₃ was then added to adjust the pH of the aqueous layer to 1-3. The layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (150 mL) and brine (150 mL). The solvent was then removed in vacuo to give a yellow solid (8.32 g), which was further purified by trituration with MeOH (100 mL) to give (XXI-a) as an off-white powder. (7.16 g, 22.5 mmol, 67%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.31 (s, 2H), 8.10 (d, J = 3.1 Hz, 1H), 8.48 (d, J = 2.2 Hz, 1H), 8 .83 (d, J = 0.4, 2.2 Hz, 1H), 9.34 (br s, 1H).

4- (5-Bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) -thiazole-2-carboxylic acid ethyl ester (XXIII-a)

To a stirred solution of (XXI-a) (4.97 g, 15.6 mmol) in dioxane (55 mL) was added ethyl thiooxamate (2.29 g, 17.2 mmol). The reaction mixture was stirred vigorously at 95 ° C. for 18 hours. The hot reaction mixture was filtered and the collected product was washed with cold dioxane (25 mL) to give the hydrobromide salt of (XXIII-a) as a yellow powder (6.08 g, 14.0 mmol, 90%). ). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.48 (t, J = 7.1 Hz, 3H), 4.52 (q, J = 7.1 Hz, 2H), 7.77 (s, 1H), 8 .05 (s, 1H), 8.43 (d, J = 1.8 Hz, 1H), 9.21 (s, 1H).

4- (5-Bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole-2-carboxylic acid (XXIII-b)

Ethyl 4- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) thiazole-2-carboxylate hydrobromide (XXIII-a) (4.03 g, 9.30 mmol) in water To a stirred solution of THF 1: 1 (50 mL), LiOH.H ₂ O (900 mg, 21.45 mmol) was added in portions over 30 minutes. After stirring for 3 hours, the reaction mixture was filtered to give a yellow solid (2.49 g). The filtrate was then concentrated to about 20 mL by evaporation and filtered again to give an additional 820 mg of a yellow solid. The solids were combined to give (XXIII-b) (3.31 g, crude yield> 100%). ¹ H NMR (400 MHz, D-6 DMSO) δ 7.76 (s, 1H), 8.03 (s, 1H), 7.73-7.78 (m, 3H), 8.32 (d, J = 2.3 Hz, 1H), 8.74 (d, J = 2.3 Hz, 1H), 12.09 (brs, 1H).

(4- (5-Bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) thiazol-2-yl) (piperidin-1-yl) methanone (XXIII-c)

Compound (XXIII-b) (1.14 g, 3.54 mmol or less), triethylamine (1.00 mL, 726 mg, 7.17 mmol), piperidine (0.70 mL, 603 mg, 7.09 mmol) and BOP in DMF (15 mL) (2.25 g, 5.09 mmol) was converted to (XXIII-c) by stirring for 18 hours followed by following the general procedure for amide formation. The crude reaction mixture was treated with AcOEt (100 mL), washed with NaHCO ₃ (2 × 50 mL), concentrated and purified by SGC using MeOH: CH ₂ Cl ₂ = 1: 19 (v / v). Crude (XXIII-c) was obtained as an off-white powder (1.26 g, 3.52 mmol or less), which was used in subsequent reactions without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.72-1.91 (m, 6H), 3.78-3.84 (m, 2H), 4.39-4.45 (m, 2H), 7 .54 (s, 1H), 7.80 (s, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 2.0 Hz, 1H), 9.25 (S, 1H).

(4- (5-Bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) thiazol-2-yl) (morpholino) methanone (XXIII-d)

Compound (XXIII-b) (0.85 g, 2.62 mmol or less), triethylamine (0.70 mL, 508 mg, 5.02 mmol), morpholine (448 mg, 5.14 mmol) and BOP (1.60 g) in DMF (10 mL) 3.62 mmol) was converted to (XXIII-d) by stirring for 4 days and following the general procedure for amide formation. The crude reaction mixture was treated with AcOEt (100 mL) and washed with NaHCO ₃ (3 × 25 mL). Upon standing, a precipitate formed in the aqueous layer, which was filtered to give crude (XXIII-d) as a white powder (1.96 g, crude yield> 100%), which was further purified. Used in subsequent reaction. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.67 to 3.84 (m, 6H), 4.40 to 4.50 (m, 2H), 8.18 (s, 1H), 8.22 (S, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.59 (d, J = 2.2 Hz, 1H).

(4- (5-Bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) thiazol-2-yl) (4-methylpiperazin-1-yl) methanone (XXIII-e)

Compound (XXIII-b) (1.46 g, 4.10 mmol or less), triethylamine (1.30 mL, 944 mg, 9.33 mmol), -methyl-piperazine (1.00 mL, 903 mg, 9.01 mmol) in DMF (20 mL) ) And BOP (2.70 g, 6.10 mmol) were converted to (XXIII-e) by stirring for 4 days and following the general procedure for amide formation. The crude reaction mixture was treated with AcOEt (100 mL), extracted with NaHCO ₃ (3 × 50 mL) and evaporated to give crude (XXIII-e) as an off-white powder (1.80 g, 4.43 mmol or less). This was used in subsequent reactions without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.26 (s, 3H), 2.41 to 2.48 (m, 2H), 2.93 to 3.04 (m, 2H), 3.67 ˜3.75 (m, 2H), 4.35 to 4.43 (m, 2H), 8.19 (d, J = 2.6 Hz, 1H), 8.23 (s, 1H), 8.37 (D, J = 2.2 Hz, 1H), 8.64 (d, J = 2.2 Hz, 1H).

4- [4- (5-Bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) -thiazol-2-yl] -piperidine-1-carboxylic acid tert-butyl ester (XXIII-f)

To a solution of (XXI-a) (1.71 g, 5.38 mmol) in THF (20 mL) was added 1-Boc-4-aminothiocarbonylpiperidine (1.31 g, 5.36 mmol) and the solution was at room temperature for 3 hours. Stir. The reaction mixture was then poured into saturated aqueous NaHCO ₃ (50 mL) and extracted with AcOEt (2 × 50 mL). The combined organic extracts were then evaporated to give (XXIII-f) (2.58 g, 5.41 mmol, 100%) as a white powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.43 (s, 9H), 1.64 to 1.84 (m, 4H), 2.07 to 2.17 (m, 2H), 2.81 to 2 .94 (m, 2H), 3.13-3.24 (m, 1H), 7.17 (s, 1H), 7.74 (d, J = 2.4 Hz, 1H), 8.32 (d , J = 2.1 Hz, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.97 (brs, 1H).

4- (5-Bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) -N, N-diethylthiazol-2-amine (XXIII-i)

To a stirred solution of (XXI-a) (2.30 g, 7.24 mmol) in 1,4-dioxane (20 mL) was added N, N-diethylthiourea (1.00 g, 7.56 mmol) and the reaction mixture was at room temperature. Stir overnight. After 24 hours, NaHCO ₃ (saturated aqueous solution, 50 mL) was added and the solution was extracted with AcOEt (2 × 75 mL). The combined organic portions were dried over MgSO ₄ and evaporated to give the crude product (2.97 g, estimated purity 85%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.32 (t, J = 7.2 Hz, 6H), 3.59 (q, J = 7.1 Hz, 4H), 6.55 (s, 1H), 7 .75 (d, J = 2.6 Hz, 1H), 8.38 (d, J = 2.1 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H), 9.13 (br s , 1H).

4- (5-Bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) -2-methylthiazole (XXIII-k)

To a stirred solution of (XXI-a) (2.89 g, 9.09 mmol) in THF (25 mL) was added thioacetamide (0.69 g, 9.18 mmol) and the reaction mixture was heated to reflux. After 6 hours, the reaction mixture was cooled, diluted with AcOEt (200 mL) and washed with saturated aqueous solution (3 × 25 mL). The organic layer was dried (MgSO _4), and concentrated to give (XXIII-k) as a yellow powder (2.63g, 8.94mmol, 98%) . ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.73 (s, 3H), 7.12 (s, 1H), 7.73 (d, J = 2.7 Hz, 1H), 8.32 (d, J = 2.1 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.93 (brs, 1H).

tert-Butyl 2- (4- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) thiazol-2-yl) pyrrolidine-1-carboxylate (XXIII-o)

To a solution of (XXI-a) (2.80 g, 8.81 mmol) in THF (80 mL), tert-butyl 2-carbamothioylpyrrolidine-1-carboxylate (3.04 g, 13.21 mmol) was added and the solution was added. Heated to reflux overnight. Cooled and then poured into saturated aqueous NaHCO ₃ (100 mL) and extracted with AcOEt (3 × 100 mL). The combined organic extracts were dried over MgSO ₄ and concentrated. The crude product was purified by SCG using 0% to 100% EtOAc: hexane (0: 100 to 100: 0, v / v gradient) as eluent to give product (XXIII-o) (2. 44 g, 61%) was obtained as a yellow foam. The compound exists as a rotamer. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.36 (s, 6H), 1.51 (s, 3H), 1.93 to 2.08 (m, 2H), 2.28 to 2.46 (m , 2H), 2.46 to 2.61 (m, 1H), 3.64 to 3.73 (m, 1H), 5.23 (d, J = 6 Hz, 0.6H), 5.32 to 5 .37 (br s, 0.4H), 7.15 (s, 0.4H), 7.23 (s, 0.6H), 7.76 (s, 0.4H), 7.84 (s, 0.6H), 8.37 (s, 0.4H), 8.40 (s, 0.6H), 8.50 (s, 0.4H), 8.55 (s, 0.6H), 10 79 (br s, NH, 0.4H), 10.84 (br s, NH, 0.6H).

5-Cyclohexyl-1H-pyrrolo [2,3-b] pyridine (XXVb-6)

Compound (XXVa-12) was hydrogenated using the general procedure for hydrogenation of 7-azaindole. Therefore, (XXVa-12) (1.50 g, 7.57 mmol), methanol (100 mL) and 20% Pd (OH) ₂ / C (Degussa type) (0.25 g) were stirred at room temperature under H _{2 for} 4 days. did. Filtration through a pad of celite with MeOH: CH ₂ Cl ₂ = 1: 1 (200 mL) and concentration of the filtrate gave (XXVb-6) as a brown solid (1.37 g, 6.84 mmol, 90%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.24 to 1.59 (m, 5H), 1.76 to 2.00 (m, 5H), 2.66 (tt, J 3.4, 11.6 Hz) , 1H), 6.48 (d, J 3.4 Hz, 1H), 7.33 (d, J = 3.4 Hz, 1H), 7.81 (d, J = 1.8 Hz, 1H), 8. 22 (d, J = 1.8 Hz, 1H), 9.58 (brs, 1H).

5-Cyclohexenyl-1H-pyrrolo [2,3-b] pyridine (XXVa-12)

(XIX-a) (2.90 g, 14.70 mmol), cyclohexenylboronic acid pinacol ester (3.40 g, 16.34 mmol), PdCl ₂ (PPh ₃ ) ₂ (EtOH (30 mL) and toluene (30 mL). 0.52 g, 0.74 mmol), LiCl (1.87 g, 44.11 mmol), and 1.0 M Na ₂ CO ₃ aqueous solution (20 mL, 20 mmol) were used using the general procedure A for the Suzuki reaction. For 4 hours. The crude product (5.74 g; dark brown oil) was purified by SGC using ethyl acetate: CH ₂ Cl ₂ = 1: 4 (v / v) as eluent to give (XXVa-12) light Obtained as a yellow powder (1.50 g, 7.57 mmol, 51%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.68-1.75 (m, 2H), 1.81-1.88 (m, 2H), 2.23-2.29 (m, 2H), 2 .47 to 2.53 (m, 2H), 6.10 to 6.14 (m, 1H), 6.50 (dd, J 2.0, 3.5 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 1.7 Hz, 1H), 8.40 (d, J = 1.8 Hz, 1H), 7.88 (s, 1H), 9.07 (Br s, 1H).

5- (1,4-Dioxa-spiro [4.5] dec-8-yl) -1H-pyrrolo [2,3-b] pyridine (XXVb-23)

Compound (XXVa-36) was hydrogenated using the general procedure for hydrogenation of 7-azaindole. Hence, (XXVa-36) (800 mg, 3.12 mmol), methanol (100 mL) and _CH 2 _Cl 2 (10 mL), and 10% Pd / C (catalytic amount) at room temperature under _{H 2} for 16.5 hours Stir. Filter through a pad of celite with MeOH: CH ₂ Cl ₂ and concentrate the filtrate to give (XXVb-23) as a white solid (795 mg, 99%); ¹ H NMR (400 MHz, CDCl ₃ ). δ 1.70-1.80 (m, 2H), 1.86-2.00 (m, 6H), 2.72 (m, 1H), 4.01 (s, 4H), 6.46 (dd , J = 1.4, 3.4 Hz, 1H), 7.34 (m, 1H), 7.84 (d, J = 1.5 Hz, 1H), 8.25 (bs, 1H), 10.21. (Bs, NH).

5- (1,4-Dioxa-spiro [4.5] dec-8-yl) -1H-pyrrolo [2,3-b] pyridine (XXVb-23) —an alternative method of preparation

To a stirred solution of azaindole (XXVIIb-23) (4.23 g, 11.4 mmol) in THF (50 mL) was added 1M nBu ₄ NF in THF (22.7 mL, 22.7 mmol). After 75 minutes, the mixture was concentrated and separated by SGC using hexane: AcOEt (100: 0 to 0: 100, v / v gradient) as eluent to give azaindole (XXVb-23) (2.51 g 86%), which was indistinguishable by NMR from the compound prepared previously by reduction of (XXVa-36).

5- (1,4-Dioxa-spiro [4.5] dec-7-en-8-yl) -1H-pyrrolo [2,3-b] pyridine (XXVa-36)

(XIX-a) (1.00 g, 5.08 mmol), boronic ester (VIb-36) (2.15 g, 8.07 mmol), PdCl ₂ (PPh ₃ ) in EtOH (25 mL) and toluene (25 mL) _A mixture of ₂ (378 mg, 0.54 mmol), LiCl (684 mg, 16.1 mmol), and 1.0 M aqueous Na ₂ CO ₃ (13.5 mL, 13.5 mmol) was added to the general procedure A for Suzuki reaction. For 3.5 hours. The crude product was purified by SGC using ethyl acetate: hexane = 6: 4 (v / v) as eluent (gradient elution) to give a brown solid. This solid was washed with 10%, then 20%, and finally 30% ethyl acetate in hexanes to give (XXVa-36) (881 mg, 68%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.98 (t, J = 6.46 Hz, 2H), 2.52 (m, 2H), 2.76 (m, 2H), 4.06 (s, 4H ), 6.00 (m, 1H), 6.49 (dd, J = 1.9, 3.46 Hz, 1H), 7.33 (t, J = 2.91 Hz, 1H), 7.94 (d , J = 1.97 Hz, 1H), 8.42 (d, J = 2.1 Hz, 1H), 9.88 (bs, NH).

4- (4- (1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohex-3-enyl) morpholine (XXVa-54)

(XIX-a) (18.00 g, 91.35 mmol), boronate ester (VIb-54) (31.40 g, 107.09 mmol), PdCl ₂ (PPh ₃ ) ₂ (3.21 g, 4.57 mmol), A mixture of LiCl (11.62 g, 274.06 mmol), and 1.0 M Na ₂ CO ₃ aqueous solution (91.4 mL, 91.4 mmol) in EtOH (150 mL) and toluene (150 mL) was added to a general solution for the Suzuki reaction. The reaction was performed using Procedure A for 5 hours. The reaction mixture was cooled and poured into AcOEt (500 mL) and saturated aqueous NaHCO ₃ (200 mL). The layers were separated and left overnight. After 18 hours, the aqueous layer was filtered to give (XXVa-54) as a pale brown powder (13.59 g). The aqueous filtrate was then further extracted with AcOEt (500 mL) and the combined organic portions were dried over MgSO ₄ and evaporated to give a dark brown oil (33.37 g), which was triturated with MeOH (250 mL). Further, (XXVa-54) was obtained as a light brown powder (2.76 g). Total yield of (XXVa-54) 17.23 g (60.80 mmol, 63%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.57 to 1.73 (m, 1H), 2.17 to 2.31 (m, 2H), 2.44 to 2.75 (m, 8H), 3 .80 (t, J = 4.6 Hz, 4H), 6.05 to 6.09 (m, 1H), 6.50 (dd, J = 2.0, 3.5 Hz, 1H), 7.31 ( dd, J = 2.5, 3.4 Hz, 1H), 7.92 (d, J = 1.9 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H), 8.82 (br s, 1H).

4-((1r, 4r) -4- (1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepane (XXVb-75)

Azaindole (XXVIIb-75) (1.5 g, 3.6 mmol) in MeOH (80 mL) and 12 M HCl (1.50 mL, 18.0 mmol) was prepared according to General Procedure B for 7-azaindole deprotection. And deprotected for 45 minutes to give azaindole (XXVb-75) (1.27 g) as an off-white powder that was used directly in the next conversion without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.42 to 1.65 (m, 4H), 1.84 to 1.92 (m, 2H), 1.97 to 2.06 (m, 4H), 2 .56 to 2.70 (m, 2H), 3.73 to 3.75 (m, 2H), 3.82 (t, J = 6.0 Hz, 2H), 6.43 (q, J = 2. 0 Hz, 1H), 7.29 (q, J = 2.5 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 9.35 (br s, 1H).

4- (4- (1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohex-3-enyl) -1,4-oxazepane (XXVa-101)

(XIX-a) (10 g, 50.8 mmol), boronic ester (VIb-101) (17.15 g, 55.8 mmol), PdCl ₂ (PPh ₃ ) ₂ (EtOH (200 mL) and toluene (200 mL). A mixture of 3.92 g, 5.6 mmol), LiCl (6.93 g, 163.4 mmol), and 1.0 M aqueous Na ₂ CO ₃ solution (137 mL, 137 mmol) was used using General Procedure A for the Suzuki reaction. For 2.5 hours. The reaction mixture was cooled and partitioned between saturated brine (100 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (3 × 150 mL). The combined organic solution was dried (MgSO ₄ ), filtered and concentrated to give an orange powder. This was triturated with cold EtOAc and filtered to give the Suzuki adduct (XXVa-101) (12.65 g, 84%) as a tan solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.64 to 1.74 (m, 1H), 1.89 to 1.92 (m, 2H), 2.10 (m, 1H), 2.20 to 2 .27 (m, 1H), 2.39-2.46 (m, 1H), 2.60-2.64 (m, 2H), 2.86 (m, 4H), 2.95 (m, 1H) ), 3.76 (t, J = 4.6 Hz, 2H), 3.83 (t, J = 6.0 Hz, 2H), 6.05 (m, 1H), 6.4 (dd, J = 2) 0.0, 3.5 Hz, 1H), 7.29-7.30 (m, 1H), 7.89 (d, J = 2.0 Hz, 1H), 8.37 (d, J = 2.0 Hz, 1H), 9.21 (br s, 1H).

5-Cyclohexyl-3-iodo-1H-pyrrolo [2,3-b] pyridine (XXVIb-6)

To a solution of (XXVb-6) (1.37 g, 6.84 mmol) in DMF (30 mL) was added KOH (0.77 g, 13.68 mmol) and the mixture was stirred for 5 minutes. Iodine (1.77 g, 6.98 mmol) was then partially added over 10 minutes and the reaction was stirred at room temperature for 2 hours. The solution was then diluted with AcOEt (250 mL) and washed with saturated aqueous Na ₂ S ₂ O ₃ (2 × 50 mL). The organic layer was dried (MgSO ₄ ) and concentrated to give (XXVIb-6) (1.92 g, 5.89 mmol, 86%) as a yellow powder. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.27 to 1.61 (m, 5H), 1.78 to 2.00 (m, 5H), 2.70 (tt, J = 3.3, 11. 5 Hz, 1 H), 7.40 (d, J = 2.0 Hz, 1 H), 7.57 (d, J = 2.0 Hz, 1 H), 8.22 (d, J = 2.0 Hz, 1 H), 8.95 (br s, 1H).

3-Iodo-5- (1,4-dioxaspiro [4.5] decan-8-yl) -1H-pyrrolo [2,3-b] pyridine (XXVIb-23)

To a stirred mixture of azaindole (XXVb-23) (2.51 g, 9.72 mmol) and ground KOH pellets (2.05 g, 36.6 mmol) in DMF (40 mL) was added iodide (2.22 g, 8.7 mmol). added. After 3.5 hours, the mixture was concentrated and partitioned between EtOAc (100 mL) and saturated NaHCO3 solution (40 mL). The aqueous layer was extracted with EtOAc (3 × 60 mL) and the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated to give the crude iodide (XXVIb-23), which did not undergo any purification. Used directly for further processing.

4-((1r, 4r) -4- (3-iodo-1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepane (XXVIb-75)

To a stirred mixture of (XXVb-75) (1.09 g, 3.6 mmol) and solid KOH (0.77 g, 13.7 mmol) in DMF (40 mL) was added iodide (0.83 g, 3.3 mmol), The mixture was stirred for 3 hours. The reaction mixture was partially concentrated in vacuo and partitioned between EtOAc (100 mL) and saturated NaHCO ₃ (40 mL). The aqueous layer was extracted with EtOAc (3 × 60 mL). The combined organic solution was dried (MgSO ₄ ) and concentrated to give iodide (XXVIb-75), which was used directly for further steps without any further purification. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 1.42~1.52 (m, 2H), 1.56~1.67 (m, 2H), 1.84~1.91 (m, 2H), 1 .98 to 2.04 (m, 4H), 2.59 to 2.71 (m, 2H), 2.81 to 2.85 (m, 4H), 3.73 to 3.75 (m, 2H) 3.81 (t, J = 6.0 Hz, 2H), 7.39 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 8.18 ( d, J = 2.0 Hz, 1H), 9.83 (brs, 1H).

1- (tert-Butyldimethylsilyl) -5- (1,4-dioxaspiro [4.5] decan-8-yl) -1H-pyrrolo [2,3-b] pyridine (XXVIIb-23)

Compound (XXVIIa-36) was hydrogenated using the general procedure for hydrogenation of 7-azaindole. Therefore, (XXVIIa-36) (4.37 g, 11.8 mmol), EtOH (35 mL) and THF (35 mL), and Pd (OH) ₂ (20% on carbon, Degussa form) (1.00 g) Stir at room temperature under H _{2 for} 24 hours. Filtration through a pad of celite with EtOH (500 mL), AcOEt (500 mL) and the filtrate was concentrated to give (XXVIIb-23) (4.23 g, 96%).

4-((1s, 4s) -4- (1- (tert-butyldimethylsilyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (XXVIIb-28) and 4- ( (1r, 4r) -4- (1- (tert-Butyldimethylsilyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) morpholine (XXVIIb-29)

Compound (XXVIIa-54) was hydrogenated using the general procedure for hydrogenation of 7-azaindole. Therefore, (XXVIIa-54) (11.00 g, 27.66 mmol), ethanol (100 mL) and THF (100 mL), and Pd (OH) ₂ (20% on carbon, Degussa form) (2.00 g) Stir at room temperature under H _{2 for} 22 hours. Filtration through a pad of celite with ethanol (500 mL) and concentration of the filtrate gave a crude mixture of cis and trans isomers. The isomers were separated by SGC using AcOEt: CH ₂ Cl ₂ (1: 2 to 2: 1 v / v gradient) to give (XXVIIb-28) (4.08 g, 10.21 mmol, 37%), Then (XXVIIb-29) (6.67 g, 16.69 mmol, 60%) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.56 (s, 6H), 0.87 (s, 9H), 1.30 to 1.65 (m, 5H), 1.89 to 2.13 (m , 4H), 2.38 to 2.76 (m, 5H), 3.58 to 3.94 (m, 4H), 6.42 (d, J = 3.5 Hz, 1H), 7.16 (d , J = 3.5 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H).

1- (tert-Butyldimethylsilyl) -5- (1,4-dioxaspiro [4.5] dec-7-en-8-yl) -1H-pyrrolo [2,3-b] pyridine (XXVIIa-36)

To a solution of azaindole (XXVa-36) (4.0 g, 15.6 mmol) in DMF (35 mL) was added NaH (0.749 g, 18.7 mmol; 60% in oil) in one portion. After 10 minutes, tetrabutyldimethylsilyl chloride (3.06 g, 20.3 mmol) was added in two portions over 1 minute. After an additional 19.5 hours, the mixture was diluted with EtOAc (100 mL) and saturated aqueous NaHCO ₃ (35 mL) and partitioned. The aqueous layer was extracted with EtOAc (2 × 40 mL). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated to give a golden viscous oil. This was purified by SGC using hexane: AcOEt (gradient elution) to give the silylated derivative (XXVIIa-36) (4.37 g, 76%).

4- (4- (1- (tert-butyldimethylsilyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohex-3-enyl) morpholine (XXVIIa-54)

To a solution of (XXVa-54) (17.23 g, 60.80 mmol) in DMF (250 mL) was added NaH (2.67 g, 60% in mineral oil, 66.67 mmol) in portions over 30 minutes. The reaction mixture was allowed to stir for 10 minutes and then tert-butyldimethylchlorosilane (11.00 g, 72.96 mmol) was added portionwise over 10 minutes. After stirring at room temperature for 3 days, the reaction was quenched with saturated aqueous NaHCO ₃ (250 mL) and extracted with AcOEt (800 mL). The organic layer was further washed with saturated aqueous NaHCO ₃ (2 × 250 mL), dried over MgSO ₄ and concentrated to give an oil (17.45 g). The crude product was purified by flash column chromatography to give (XXVIIa-54) (11.00 g, 27.66 mmol, 46%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.60 (s, 6H), 0.89 (s, 9H), 1.53 to 1.64 (m, 1H), 2.10 to 2.25 (m , 2H), 2.37 to 2.68 (m, 8H), 3.74 (t, J = 4.7 Hz, 4H), 5.99 to 6.03 (m, 1H), 6.46 (d , J = 3.4 Hz, 1H), 7.18 (d, J = 3.5 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 8.32 (d, J = 2. 3Hz, 1H).

4-((1r, 4r) -4- (1- (tert-butyldimethylsilyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepane (XXVIIb-75 ) And 4-((1s, 4s) -4- (1- (tert-butyldimethylsilyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1,4-oxazepane (XXVIIb -76)

Compound (XXVIIa-101) was hydrogenated using the general procedure for hydrogenation of 7-azaindole. Therefore, (XXVIIa-101) (15.37 g, 37.3 mmol), ethanol (120 mL) and THF (120 mL), and Pd (OH) ₂ (20% on carbon, Degussa form) (3.50 g) Stir at room temperature under H _{2 for} 23 hours. Another catalyst (2.00 g) was added and stirring was continued under H _{2 for} 23.5 hours. Filter through a pad of celite with EtOH (500 mL), EtOAc (500 mL), DCM (500 mL), 10% MeOH / DCM (500 mL) and 10% MeOH / EtOAc (300 mL) and concentrate the filtrate to cis and A crude mixture of trans isomers (15.44 g) was obtained as a viscous golden oil. Isomers were separated by SGC using AcOEt: MeOH = 9: 1 (v / v) to give (XXVIIb-76) (5.91 g, 38%), then mixed fractions (2.01 g, 13%) And (XXVIIb-75) (4.19 g, 27%).

Data of trans isomer (XXVIIb-75): ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.62 (s, 6H), 0.93 (s, 9H), 1.42 to 1.62 (m, 4H) ), 1.88 (m, 1H), 1.99 to 2.02 (m, 4H), 2.52 to 2.66 (m, 2H), 2.83 (m, 4H), 3.74 ( m, 12H), 3.82 (t, J = 6.0 Hz, 2H), 6.46 (d, J = 3.4 Hz, 1H), 7.20 (d, J = 3.4 Hz, 1H), 7.67 (d, J = 2.1 Hz, 1H), 8.14 (d, J = 2.1 Hz, 1H).

4- (4- (1- (tert-butyldimethylsilyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohex-3-enyl) -1,4-oxazepane (XXVIIa-101)

To a stirred solution of azaindole (XXVa-101) (12.65 g, 42.5 mmol) in DMF (120 mL) was added 60% NaH dispersion in mineral oil (2.04 g, 51.0 mmol) in portions over 3 minutes. After 15 minutes, tert-butyldimethylchlorosilane (8.33 g, 55.3 mmol) was added and the mixture was stirred for an additional 66 hours. The mixture was diluted with EtOAc (150 mL) and saturated NaHCO ₃ solution (100 mL) and partitioned. The aqueous layer was extracted with EtOAc (4 × 150 mL) and CH ₂ Cl ₂ (100 mL). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated to give a golden viscous oil. This consists of hexane: CH ₂ Cl ₂ (100: 0 to 0: 100, v / v gradient elution) followed by CH ₂ Cl ₂ : MeOH (100: 0 to 90:10, v / v gradient elution). Purification by SGC used gave silylated azaindole (XXVIIa-101) (15.37 g, 87%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.62 (s, 6H), 0.92 (s, 9H), 1.68 (m, 1H), 1.87 to 1.93 (m, 2H), 2.05 to 2.10 (m, 1H), 2.18 to 2.26 (m, 1H), 2.36 to 2.43 (m, 1H), 2.57 to 2.63 (m, 2H) ), 2.83 to 2.86 (m, 5H), 3.75 (t, J = 4.7 Hz, 2H), 3.82 (t, J = 6.0 Hz, 2H), 6.02 to 6 .05 (m, 1H), 6.49 (d, J = 3.5 Hz, 1H), 7.21 (d, J = 3.5 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 8.33 (d, J = 2.3 Hz, 1H).

4-((1r, 4r) -4- (1- (tert-butyldimethylsilyl) -3- (tributylstannyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) cyclohexyl) -1 , 4-Oxazepane (XXVIIIb-75)

1.7 M tert-butyllithium in pentane (1.5 mL, 2.5 mmol) was added dropwise over 2 minutes to a solution of bromide (IXb-75) (585 mg, 1.2 mmol) in THF (5 mL) under a nitrogen atmosphere. Stir at -78 ° C. After an additional 15 minutes, iodotributyltin (0.41 mL, 1.4 mmol) was quickly added in one portion. The mixture was stirred at −78 ° C. for 40 minutes and then warmed to room temperature over 40 minutes. The mixture was partitioned between saturated aqueous NaHCO ₃ (15 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (2 × 15 mL) and the combined organic solution was dried (MgSO ₄ ) and concentrated. The residue was azeotroped from PhMe (1 × 35 mL) to give a viscous yellow oil (1.0 g) (5: 1 mixture of stannane (XXVIIIb-75) and azaindole (XXVIIb-75)), This was used for further transformations without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) spectrum: δ 0.62 (s, 6H), 0.88 (s, 9H), 0.92 (s, 9H), 1.07 to 1.11 (m, 6H) ), 1.27 to 1.39 (m, 6H), 1.45 to 1.64 (m, 10H), 1.85 to 1.91 (m, 2H), 1.96 to 2.05 (m) , 4H), 2.51 to 2.68 (m, 2H), 2.81 to 2.86 (m, 4H), 3.72 to 3.76 (m, 2H), 3.82 (t, J = 6.0 Hz, 2H), 7.08 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H).

Biological Activity JNK1, JNK2, JNK3-SPA Assay JNK1, JNK2, JNK3-SPA Assay The compound is dissolved in DMSO to a convenient concentration, which is diluted with 10% DMSO to 5 times the desired starting concentration (often 1: 100).

2. Add 10 μl of 500 mM EDTA to the replacement well in the row of the Opti plate, which contains the kinase reaction and DMSO. This is taken as a negative control.

3. In the JNK2 and JNK3 assays, compounds are prepared in 6 two-fold dilutions in water and each concentration is tested twice. In the JNK1 assay, compounds are prepared in four 5-fold dilutions in water and each concentration is tested in triplicate. Controls are treated similarly.

4. Transfer 20 μl of each compound concentration per well to Opti plate twice.

5. 30 μl (JNK2 / 3 SPA) or 50 μl (JNK1 SPA) substrate solution (25 mM HEPES pH 7.5 in water, 10 mM magnesium acetate, and 3.33 μM ATP (JNK2 / 3) or 2 μM ATP (JNK1 ), Approximately 7.5 kBq of [γ- ³³ P] ATP, GST-c-Jun) is added to each well.

6. Add 50 μl (JNK2 / 3 SPA) or 30 μl (JNK1 SPA) of kinase solution (JNK in 25 mM HEPES pH 7.5, 10 mM Mg acetate) to each well.

7). Incubate the plate for 30 minutes at room temperature.

8. Add 100 μl of bead / stop solution to each well (5 mg / ml glutathione-PVT-SPA beads, 40 mM ATP in PBS).

9. The plate is sealed, incubated for 30 minutes at room temperature, centrifuged for 10 minutes at 2500 g and counted.

10. IC ₅₀ values are calculated as the concentration of compound tested, where c-Jun phosphorylation is reduced to 50% of the control value. Example IC ₅₀ values for compounds of the invention are shown in Tables 1 and 2.

Selectivity of compound (I) for a panel of kinases ATP concentration of 10 micromolar concentrations of compounds (I-8) and (I-60) and 5 micromolar concentrations of compounds (I-69) and (I-70) 10 The inhibitory potency at micromolar was determined in Upstate / Millipore against a panel of 100 kinases representing all major families within the kinome. The results are shown in Table 3 and are expressed as a percentage of residual activity.

For comparison purposes, Table 4 contains relevant inhibition data for reference compounds AL containing a (hetero) aromatic ring in C (5) of the 7-azaindole system.

Selectivity Expressed as Gini Coefficients Selectivities of compounds according to the invention expressed as Gini coefficients (J. Med. Chem. 2007, 50, 5773-5779) and reference compounds are shown in Table 5. Individual Gini coefficients are calculated using the data in Tables 3 and 4. Gini value = 0 corresponds to a completely non-selective compound, and Gini value = 1 reflects complete selectivity (inhibition of a single target only).

Experimental protocol for LPS-induced TNFα suppression in mice Male C57 / B16 mice were studied. Compound (20 mg / kg; oral) was administered 30 minutes prior to injection of lipopolysaccharide (LPS). LPS was administered intraperitoneally at a dose of 10 mg / kg. The animals were sacrificed 1 hour after LPS injection. Blood was collected in heparinized tubes for measurement of plasma TNFα concentration and spleen was collected for measurement of c-Jun phosphorylation. Plasma TNFα was measured using an ELISA kit purchased from R & D systems. Spleens were homogenized and extracted into high salt (250 mM NaCl) lysis buffer containing phosphatase inhibitors and c-Jun phosphorylation was measured using HTRF. The inhibitory effect of the compound was calculated as the percent decrease in plasma TNFα concentration and spleen Pc-Jun concentration compared to vehicle treated animals.

Results The results are shown in Table 6.

MOG (35-55) -induced experimental autoimmune encephalomyelitis (EAE) in C57 / B16J mice
Experimental protocol Reagents PBS: 0.01 M phosphate buffer, 0.0027 M potassium chloride, 0.137 M sodium chloride pH 7.4 (prepared from tablets-Sigma, Poole, Dorset, UK)
Mycobacterium tuberculosis H37 RA: Difco Laboratories, Detroit, MOG Peptide, Michigan, USA (35-55) : Calbiochem (Merck Bioscience (UK), Beeston, Nottingham, UK)
Freund's incomplete adjuvant (Difco Laboratories, Detroit, Michigan, USA)
Animals Specific pathogen-free male C57 / B16J mice were 6-8 weeks old (20-24 g) at Charles River UK Ltd. (Margate, UK). Mice are purchased and acclimatized for at least 3 days prior to the start of the experiment. Two mice per cage in a transparent plastic cage with a wire cover (width 270 x length 370 x height 230 mm), constant temperature (20-24 ° C), constant humidity (40-70%), 12 hour light / dark cycle Enter the room (brighten from 6am to 6pm). Animals are given pellet food (RM1 E, Specialist Diet Services, Witham, UK) and tap water ad libitum.

Method MOG (35-55) adjuvant was prepared as follows.

1. Prepare a 20 ml syringe by removing the plunger and plugging the injection end with a stopper (we use the cutoff end of a Treff Pellet Mixer (2.5 ml), Anachem, Lutons, Bedfordshire, UK) 2 Add 5 ml 2 mg / ml MOG35-55 to PBS Add 5 ml Freund's incomplete adjuvant (IFA) supplemented with 3.5 mg / ml (25 mg total) Mycobacterium tuberculosis H37ra to a 20 ml syringe 4. Cover with 2 layers of parafilm and vortex the mixture for 1 minute Sonicate (15 minutes; Decon FS Minor sonicated water bath)
6. Emulsify by repeatedly passing between two 20 ml syringes (20 passes; the syringe is connected to a PVC tube and secured with a cable tie).

7). Check emulsion-Place emulsion droplets on water. The entire droplet should stay. If the droplet dissipates immediately, repeat step 5.

8. Dispense 10 ml aliquots into 10 ml syringes and keep frozen (−80 ° C.) or on ice until use.

On day 1.0 of the induction protocol, 0.1 ml of MOG (35-55) adjuvant was injected subcutaneously in two places on the lower flank of the mice. Mice are also given 30 ng pertussis toxin in 100 μl PBS intravenously or intraperitoneally.

On day 2.2, mice received 30 ng pertussis toxin in 100 μl PBS intravenously or intraperitoneally.

On day 3.7, 0.1 mL of MOG (35-55) adjuvant was injected subcutaneously into the middle two flank of the mice.

4). Mice were observed daily for clinical symptoms.

Notes The site of the adjuvant injection must not be an area involving the animal's neck. Subcutaneous site manipulation leads to induction and a reduction in peak score.

  Pertussis toxin, MTB, MOG and IFA should all be batch tested. This is because there are batches that reduce induction and peak scores.

  Animals must be greater than 20 g at the time of disease induction. Otherwise the mortality rate will be about 20% (usually less than 5%).

Chronic mouse EAE scores Animals receive two scores. One gives an accurate assessment of the animal's disability (cumulative score). The second reflects the overall severity of the animal (peak score).

Peak score = Maximum score reached reached = Total score from each section For example, if a mouse has FT, IRR, HLP, the peak score is 4 and the cumulative score is 7.

A brief description of the score Tail slightly drooping-Up to 50% of the tail is not taut.

  Sagging tail-more than 50% of the tail has no tension.

Hindlimb weakness Minor weakness in hindlimbs-gait is impaired but limbs still bear load.

  Hindlimb weakness-gait is impaired and hindlimbs cannot withstand the load.

  Extreme weakness of the hind limbs—the hind limbs cannot move through more than 50% of the stride and cannot withstand the load.

Hind limb paralysis-complete loss of hind limb movement Fore limb weakness Forelimb slight weakness-decreased forelimb grip strength.

  Forelimb weakness-decreased forelimb grip leads to forelimb movement problems.

  Very weak forelimbs-limbs still move but cannot move.

  Forelimb paralysis-complete loss of forelimb movement.

Spasticity Spasticity scores can be compared to weakness scores in disability, but by hardness rather than loss of muscle tone.

References Nicole Heijmans et al., Journal of Neuroimmunology, 167, (2005) 23-33.
Dusanka S. Skundric et al., Journal of Neuroimmunology, 136 (2003) 34-45.
S Amor et al., Journal of Immunology, 150, (1993) 5666-5672.
Baker et al., Journal of Neuroimmunology, 28, (1990) 261-271.
Results (I-60) and the results of the EAE experiment of reference aromatic compound A are shown in FIGS. The drug was administered at the onset of symptoms (score 1; sagging tail).

  FIG. 1 shows the effect of (I-60) (40 mg / kg po once / day) on peak disease scores in mouse EAE experiments.

  FIG. 2 shows the effect of (I-60) (40 mg / kg po once / day) on animal body weight in mouse EAE experiments.

  FIG. 3 shows the effect of reference compound A (20 mg / kg po once / day) on peak disease scores in mouse EAE experiments.

  FIG. 4 shows the effect of Reference Compound A (20 mg / kg po once / day) on animal body weight in mouse EAE experiments.

Claims (24)

A compound of formula (I) or a pharmaceutically acceptable salt thereof:

[Where:
Ring X represents a thiazole ring,
R ¹ is a halogen atom, an oxo group, an ethylenedioxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 hydroxyalkyl group, —C (O) OH, (C _1-6 alkyl) 5-7 membered non-aromatic optionally substituted independently with 1 to 4 substituents selected from the group consisting of amino groups, di (C _1-6 alkyl) amino groups and -Ra-Rb Represents a hydrocarbon ring group,
R ^a represents a single bond or —CH ₂ —;
R ^b is a 4- to 7-membered non-aromatic heterocyclic group optionally and independently substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C _1-6 alkyl group; Represents a C _6-10 aryl group or a 5-6 membered heteroaryl group,
R ² represents a single bond or a carbonyl group,
R ³ represents hydrogen, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 haloalkyl group, a di (C _1-6 alkyl) amino group, or a 4-7 membered non-aromatic heterocycle. Represents a ring group, wherein at least one ring heteroatom is a nitrogen atom optionally and independently substituted with 1 to 4 C _1-6 alkyl groups;
R ⁴ represents hydrogen or a C _1-6 alkyl group]. The compound of claim 1 having the formula (Ia) or a pharmaceutically acceptable salt thereof:

[Where:
Ring X, R ¹ , R ^a and R ^b are as described in claim 1,
R ² represents a single bond or a carbonyl group,
R ³ represents a hydroxyl group, a di (C _1-6 alkyl) amino group or a 4-7 membered non-aromatic heterocyclic group, wherein at least one ring heteroatom is 1 to 4 C ₁ is a nitrogen atom substituted and the independently with ₆ alkyl group]. R ¹ is composed of a halogen atom, an oxo group, an ethylenedioxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 hydroxyalkyl group, —C (O) OH, and —Ra—Rb. Represents a 5- to 7-membered non-aromatic hydrocarbon ring group optionally and independently substituted with 1 to 4 substituents selected from the group;
Ring X, R ^a , R ^b , R ² and R ³ are as defined in claim 2;
The compound according to claim 2 or a pharmaceutically acceptable salt thereof. R ¹ is a halogen atom, an oxo group, an ethylenedioxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 hydroxyalkyl group, —C (O) OH, (C _1-6 alkyl) ) A cyclopentyl group, a cyclohexyl group optionally and independently substituted with 1 to 4 substituents selected from the group consisting of an amino group, a di (C _1-6 alkyl) amino group and —R ^a —R ^b Represents a cyclopentenyl group, a cyclohexenyl group, or a cyclohexadienyl group,
R ^a represents a single bond or —CH ₂ —;
A 4- to 7-membered non-aromatic heterocyclic group, wherein R ^b is optionally and independently substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C _1-6 alkyl group; Represents a C _6-10 aryl group or a 5-6 membered heteroaryl group,
The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof. R ¹ is optionally substituted with 1 to 4 substituents selected from the group consisting of an ethylenedioxy group, a C _1-6 alkyl group and a morpholino group, and optionally substituted with a cyclopentyl group, a cyclohexyl group, a cyclo The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which represents a pentenyl group, a cyclohexenyl group, or a cyclohexadienyl group. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R ² represents a single bond. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ² represents a carbonyl group. A methyl group, a methoxy group, an ethoxy group, a trifluoromethyl group, a dimethylamino group, a piperidyl group, a piperazinyl group or a morpholino group, wherein R ³ is optionally and independently substituted with hydrogen, a C _1-6 alkyl group; 8. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. R ⁴ is hydrogen or methyl, the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 or 4 to 8,. A compound selected from the following group or a pharmaceutically acceptable salt thereof.




  A pharmaceutical composition comprising the compound according to any one of claims 1 to 10.   12. A compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 for use in medicine.   12. A compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 for the prevention and / or treatment of neurodegenerative disorders, inflammatory diseases, autoimmune diseases and / or organ failure. object.   14. A compound or pharmaceutical composition according to claim 13 wherein the neurodegenerative disorder is multiple sclerosis.   14. A compound or pharmaceutical composition according to claim 13 wherein the autoimmune disease is rheumatoid arthritis.   The compound according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 11 for preventing and / or treating diabetic nephropathy, heart failure and / or liver failure.   11. A method for preventing and / or treating a neurodegenerative disorder, inflammatory disease, autoimmune disease and / or organ failure, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10 or 12. A method comprising administering to a mammal a pharmaceutically acceptable salt thereof or the composition of claim 11.   The method according to claim 17, wherein the neurodegenerative disorder is multiple sclerosis.   The method according to claim 17, wherein the autoimmune disease is rheumatoid arthritis.   A method for preventing and / or treating diabetic nephropathy, heart failure or liver failure, comprising an effective amount of a compound according to any one of claims 1 to 10 or a composition according to claim 11. Administering to a mammal.   11. A compound or pharmaceutical according to any one of claims 1 to 10 for the manufacture of a medicament for preventing and / or treating neurodegenerative disorders, inflammatory diseases, autoimmune diseases and / or organ failure. Use of its salts acceptable.   The use according to claim 21, wherein the neurodegenerative disorder is multiple sclerosis.   The use according to claim 21, wherein the autoimmune disease is rheumatoid arthritis.   11. A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing and / or treating diabetic nephropathy, heart failure and / or liver failure. Use of.